1X0H , 2RR8 , 3FAY , 3I6X
125-523: 8826 29875 ENSG00000140575 ENSMUSG00000030536 P46940 Q9JKF1 NM_003870 NM_016721 NP_003861 NP_057930 Ras GTPase-activating-like protein IQGAP1 (IQGAP1) also known as p195 is a ubiquitously expressed protein that in humans is encoded by the IQGAP1 gene . IQGAP1 is a scaffold protein involved in regulating various cellular processes ranging from organization of
250-520: A carboxyl group, and a variable side chain are bonded . Only proline differs from this basic structure as it contains an unusual ring to the N-end amine group, which forces the CO–NH amide moiety into a fixed conformation. The side chains of the standard amino acids, detailed in the list of standard amino acids , have a great variety of chemical structures and properties; it is the combined effect of all of
375-470: A gene may be duplicated before it can mutate freely. However, this can also lead to complete loss of gene function and thus pseudo-genes . More commonly, single amino acid changes have limited consequences although some can change protein function substantially, especially in enzymes . For instance, many enzymes can change their substrate specificity by one or a few mutations. Changes in substrate specificity are facilitated by substrate promiscuity , i.e.
500-453: A Ras-GAP – its mutation in neurofibromatosis will mean that Ras is less likely to be inactivated. Ras can also be amplified, although this only occurs occasionally in tumours. Finally, Ras oncogenes can be activated by point mutations so that the GTPase reaction can no longer be stimulated by GAP – this increases the half life of active Ras-GTP mutants. Constitutively active Ras ( Ras )
625-426: A catalytic water molecule for hydrolysis of GTP to GDP. The G4 motif contains a LVGNKxDL motif, and provides specific interaction to guanine. The G5 motif contains a SAK consensus sequence. The A is alanine146, which provides specificity for guanine rather than adenine. The two switch motifs, G2 (SW1) and G3 (SW2), are the main parts of the protein that move when GTP is hydrolyzed into GDP. This conformational change by
750-497: A cell to its neighbors by clasping on to the extracellular portion of the neighbor’s cadherins. Actin binds a-catenin which binds beta-catenin which in turn binds E-cadherin . E-cadherin juts into the extracellular space to grasp the extracellular domains of neighboring E-cadherins. IQGAP1 localizes to cell-cell contacts and binds actin, b-catenin, and E-cadherin, weakening these junctions and thus decreasing cell-cell adhesion. IQGAP weakens cell adhesion by displacing a-catenin from
875-552: A combination of sequence, structure and function, and they can be combined in many different ways. In an early study of 170,000 proteins, about two-thirds were assigned at least one domain, with larger proteins containing more domains (e.g. proteins larger than 600 amino acids having an average of more than 5 domains). Most proteins consist of linear polymers built from series of up to 20 different L -α- amino acids. All proteinogenic amino acids possess common structural features, including an α-carbon to which an amino group,
1000-403: A defined conformation . Proteins can interact with many types of molecules, including with other proteins , with lipids , with carbohydrates , and with DNA . It has been estimated that average-sized bacteria contain about 2 million proteins per cell (e.g. E. coli and Staphylococcus aureus ). Smaller bacteria, such as Mycoplasma or spirochetes contain fewer molecules, on
1125-851: A detailed review of the vegetable proteins at the Connecticut Agricultural Experiment Station . Then, working with Lafayette Mendel and applying Liebig's law of the minimum , which states that growth is limited by the scarcest resource, to the feeding of laboratory rats, the nutritionally essential amino acids were established. The work was continued and communicated by William Cumming Rose . The difficulty in purifying proteins in large quantities made them very difficult for early protein biochemists to study. Hence, early studies focused on proteins that could be purified in large quantities, including those of blood, egg whites, and various toxins, as well as digestive and metabolic enzymes obtained from slaughterhouses. In
1250-447: A link between logically related but molecularly distinct cellular functions. In the above example, actin cytoskeleton rearrangement is required for proliferation ( cytokinesis during mitosis ). IQGAP1 helps cells both listen to and act on signals, playing an integral role in connecting the dots between signals for proliferation and the actual cellular response. The Ras → Raf → MEK → ERK MAPK signaling pathway plays an integral part in
1375-478: A little ambiguous and can overlap in meaning. Protein is generally used to refer to the complete biological molecule in a stable conformation , whereas peptide is generally reserved for a short amino acid oligomers often lacking a stable 3D structure. But the boundary between the two is not well defined and usually lies near 20–30 residues. Polypeptide can refer to any single linear chain of amino acids, usually regardless of length, but often implies an absence of
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#17327937725511500-514: A modulatory protein intersecting all of these pathways, IQGAP1 can couple many of them, and is also responsible for their proper propagation. Since cancer is a disease characterized by the perturbation of many of these cellular processes, IQGAP1 is a logical oncogene candidate and therapeutic target. Expression analysis has implicated IQGAP1 in colorectal , squamous cell , breast , gastric , liver , lung , and ovarian cancers, and in some of these cancers, higher IQGAP1 expression levels indicate
1625-410: A particular cell or cell type is known as its proteome . The chief characteristic of proteins that also allows their diverse set of functions is their ability to bind other molecules specifically and tightly. The region of the protein responsible for binding another molecule is known as the binding site and is often a depression or "pocket" on the molecular surface. This binding ability is mediated by
1750-404: A poor prognosis. In order for a cancer to metastasize , cells must gain migratory abilities and invade other tissues. Through Rac1/CDC42, IQGAP1 regulates cellular adhesion and actin dynamics. In normal cells IQGAP1 localizes to areas of high actin turnover. This characteristic is echoed in invasive tissues, where IQGAP1 localizes to the leading edge of migrating cells. Over-expression of IQGAP1
1875-500: A protein carries out its function: for example, enzyme kinetics studies explore the chemical mechanism of an enzyme's catalytic activity and its relative affinity for various possible substrate molecules. By contrast, in vivo experiments can provide information about the physiological role of a protein in the context of a cell or even a whole organism . In silico studies use computational methods to study proteins. Proteins may be purified from other cellular components using
2000-411: A protein is defined by the sequence of a gene, which is encoded in the genetic code . In general, the genetic code specifies 20 standard amino acids; but in certain organisms the genetic code can include selenocysteine and—in certain archaea — pyrrolysine . Shortly after or even during synthesis, the residues in a protein are often chemically modified by post-translational modification , which alters
2125-542: A protein that fold into distinct structural units. Domains usually also have specific functions, such as enzymatic activities (e.g. kinase ) or they serve as binding modules (e.g. the SH3 domain binds to proline-rich sequences in other proteins). Short amino acid sequences within proteins often act as recognition sites for other proteins. For instance, SH3 domains typically bind to short PxxP motifs (i.e. 2 prolines [P], separated by two unspecified amino acids [x], although
2250-486: A role in biological recognition phenomena involving cells and proteins. Receptors and hormones are highly specific binding proteins. Transmembrane proteins can also serve as ligand transport proteins that alter the permeability of the cell membrane to small molecules and ions. The membrane alone has a hydrophobic core through which polar or charged molecules cannot diffuse . Membrane proteins contain internal channels that allow such molecules to enter and exit
2375-406: A series of purification steps may be necessary to obtain protein sufficiently pure for laboratory applications. To simplify this process, genetic engineering is often used to add chemical features to proteins that make them easier to purify without affecting their structure or activity. Here, a "tag" consisting of a specific amino acid sequence, often a series of histidine residues (a " His-tag "),
2500-450: A several Å gap between the molecules, and a high-throughput in silico docking was performed for finding gluing agents. As a proof of concept, two novel molecules were described with satisfying biological activity. In most of the cell types of most species, most Ras is the GDP type. This is true for Xenopus oocytes and mouse fibroblasts . As mentioned above most X. oocyte Ras is
2625-432: A solution known as a crude lysate . The resulting mixture can be purified using ultracentrifugation , which fractionates the various cellular components into fractions containing soluble proteins; membrane lipids and proteins; cellular organelles , and nucleic acids . Precipitation by a method known as salting out can concentrate the proteins from this lysate. Various types of chromatography are then used to isolate
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#17327937725512750-453: A treatment based on siRNA anti-mutated K-RAS (G12D) called siG12D LODER is currently in clinical trials for the treatment of locally advanced pancreatic cancer (NCT01188785, NCT01676259). In glioblastoma mouse models SHP2 levels were heightened in cancerous brain cells. Inhibiting SHP2 in turn inhibited Ras dephosphorylation. This reduced tumor sizes and accompanying rise in survival rates. Other strategies have attempted to manipulate
2875-590: A unique ability to potentially couple diverse cellular functions. For example IQGAP1 is associated with actin dynamics through direct binding of actin and indirect regulation via Cdc42/Rac1, but also modulates the MAPK pathway which is associated with cell cycle control. Thus IQGAP1 may couple MAPK signaling (decisions about cell fate ) to the cytoskeleton or cellular adhesion (potentially acting out those decisions)—an important implication for cancer. To simplify, due to its diverse range of binding partners, IQGAP1 may act as
3000-441: A variety of techniques such as ultracentrifugation , precipitation , electrophoresis , and chromatography ; the advent of genetic engineering has made possible a number of methods to facilitate purification. To perform in vitro analysis, a protein must be purified away from other cellular components. This process usually begins with cell lysis , in which a cell's membrane is disrupted and its internal contents released into
3125-559: A water molecule is optimally positioned for nucleophilic attack on the gamma-phosphate of GTP. An inorganic phosphate is released and the Ras molecule is now bound to a GDP. Since the GDP-bound form is "off" or "inactive" for signaling, GTPase Activating Protein inactivates Ras by activating its GTPase activity. Thus, GAPs accelerate Ras inactivation . GEFs catalyze a "push and pull" reaction which releases GDP from Ras. They insert close to
3250-561: Is 'switched on' by incoming signals, it subsequently switches on other proteins, which ultimately turn on genes involved in cell growth , differentiation , and survival . Mutations in Ras genes can lead to the production of permanently activated Ras proteins, which can cause unintended and overactive signaling inside the cell, even in the absence of incoming signals. Because these signals result in cell growth and division, overactive Ras signaling can ultimately lead to cancer . The three Ras genes in humans ( HRAS , KRAS , and NRAS ) are
3375-484: Is a family of related proteins that are expressed in all animal cell lineages and organs. All Ras protein family members belong to a class of protein called small GTPase , and are involved in transmitting signals within cells ( cellular signal transduction ). Ras is the prototypical member of the Ras superfamily of proteins, which are all related in three-dimensional structure and regulate diverse cell behaviours. When Ras
3500-409: Is a 190 kDa protein with 5 domains. A protein domain is a subsection of a protein that shows up multiple times in biology and can exist independently of the surrounding protein. It is very similar to subsections of other proteins, and could be cut out of the current protein, exist and function by itself, or be pasted in to a new protein strand and still function properly. Since this area of the protein
3625-521: Is a major building block of every eukaryotic cell’s cytoskeleton. Actin dynamics play a major role in cell motility (filaments are built at the leading edge of a moving cell and deconstructed at the receding edge). IQGAP1 binds actin and influences actin dynamics by localizing to the leading edge and recruiting actin polymerization machinery. IQGAP1 binds and is a target of the Rho GTPases CDC42 and RAC1 which are well known regulators of
3750-497: Is a protein-protein interaction domain that associates with proline-rich regions of other proteins. The WW domain is followed by 4 IQ motifs which form an IQ domain. This domain binds calmodulin , a protein known as a calcium sensor that can bind and regulate many target proteins. A GRD (rasGAP-related domain) follows the IQ domain. This domain is highly similar to the functional subunit of Ras GTPase-activating proteins (GAPs) and
3875-449: Is a single-subunit small GTPase , which is related in structure to the G α subunit of heterotrimeric G proteins (large GTPases). G proteins function as binary signaling switches with "on" and "off" states. In the "off" state it is bound to the nucleotide guanosine diphosphate (GDP), while in the "on" state, Ras is bound to guanosine triphosphate (GTP), which has an extra phosphate group as compared to GDP. This extra phosphate holds
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4000-414: Is a type II herpes simplex virus (HSV-2) based agent, designated FusOn-H2. Activating mutations of the Ras protein and upstream elements of the Ras protein may play a role in more than two-thirds of all human cancers, including most metastatic disease. Reolysin , a formulation of reovirus, and FusOn-H2 are currently in clinical trials or under development for the treatment of various cancers. In addition,
4125-439: Is attached to one terminus of the protein. As a result, when the lysate is passed over a chromatography column containing nickel , the histidine residues ligate the nickel and attach to the column while the untagged components of the lysate pass unimpeded. A number of different tags have been developed to help researchers purify specific proteins from complex mixtures. Ras subfamily Ras , from " Ra t s arcoma virus",
4250-505: Is conserved in amino acid sequence and structure, it can be characterized by function or binding partner. IQGAP1 has 5 well-known domains separated by other amino acids. Starting at the N-terminus (or front of the protein), IQGAP1 contains a calponin homology domain (CHD), which mediates actin-binding and binds calponin . The WW, or poly-proline protein-protein domain , so named because of two functionally conserved tryptophans, W,
4375-562: Is dictated by the nucleotide sequence of their genes , and which usually results in protein folding into a specific 3D structure that determines its activity. A linear chain of amino acid residues is called a polypeptide . A protein contains at least one long polypeptide. Short polypeptides, containing less than 20–30 residues, are rarely considered to be proteins and are commonly called peptides . The individual amino acid residues are bonded together by peptide bonds and adjacent amino acid residues. The sequence of amino acid residues in
4500-529: Is facilitated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). As per its classification, Ras has an intrinsic GTPase activity, which means that the protein on its own will hydrolyze a bound GTP molecule into GDP. However this process is too slow for efficient function, and hence the GAP for Ras, RasGAP, may bind to and stabilize the catalytic machinery of Ras, supplying additional catalytic residues (" arginine finger ") such that
4625-628: Is found in hard or filamentous structures such as hair , nails , feathers , hooves , and some animal shells . Some globular proteins can also play structural functions, for example, actin and tubulin are globular and soluble as monomers, but polymerize to form long, stiff fibers that make up the cytoskeleton , which allows the cell to maintain its shape and size. Other proteins that serve structural functions are motor proteins such as myosin , kinesin , and dynein , which are capable of generating mechanical forces. These proteins are crucial for cellular motility of single celled organisms and
4750-413: Is found in many effectors and invariably binds to one of the switch regions, because these change conformation between the active and inactive forms. However, they may also bind to the rest of the protein surface. Other proteins exist that may change the activity of Ras family proteins. One example is GDI (GDP Disassociation Inhibitor). These function by slowing the exchange of GDP for GTP, thus prolonging
4875-444: Is found throughout the cell as well as throughout tissue types. Expression analysis has also indicated that IQGAP1 is overexpressed in many cancers, and in more aggressive colorectal and ovarian cancers, IQGAP1 is localized at the invasive front of the neoplasm, indicating a role in mobilization of the cells. Importantly, approximately 10% of genes that show increased expression in metastatic cells are IQGAP1 binding partners. IQGAP1
5000-469: Is higher in prokaryotes than eukaryotes and can reach up to 20 amino acids per second. The process of synthesizing a protein from an mRNA template is known as translation . The mRNA is loaded onto the ribosome and is read three nucleotides at a time by matching each codon to its base pairing anticodon located on a transfer RNA molecule, which carries the amino acid corresponding to the codon it recognizes. The enzyme aminoacyl tRNA synthetase "charges"
5125-558: Is important in cancer. Protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues . Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions , DNA replication , responding to stimuli , providing structure to cells and organisms , and transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which
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5250-699: Is in neural cells. The gene in C. elegans is let 60 . Also appears to play a role in receptor tyrosine kinase formation in this model. Overexpression yields a multivulval development due to its involvement in that region's normal development; overexpression in effector sites in lethal. Essential in Dictyostelium discoideum . This is evidenced by severe developmental failure in deficient ras expression and by significant impairment of various life activities when artificially expressed, such as: increased concentration of inositol phosphates ; likely reduction of cAMP binding to chemotaxis receptors; and that
5375-461: Is inefficient for polypeptides longer than about 300 amino acids, and the synthesized proteins may not readily assume their native tertiary structure . Most chemical synthesis methods proceed from C-terminus to N-terminus, opposite the biological reaction. Most proteins fold into unique 3D structures. The shape into which a protein naturally folds is known as its native conformation . Although many proteins can fold unassisted, simply through
5500-464: Is involved in cell growth and differentiation). Reovirus replicates in and eventually kills Ras-activated tumour cells and as cell death occurs, progeny virus particles are free to infect surrounding cancer cells. This cycle of infection, replication and cell death is believed to be repeated until all tumour cells carrying an activated Ras pathway are destroyed. Another tumor-lysing virus that specifically targets tumor cells with an activated Ras pathway
5625-434: Is necessary for neuronal process outgrowth on the cell adhesion molecule PTPmu ( PTPRM ). Expression of the protein is upregulated by gene amplification in two gastric cancer cell lines and its over-expression and distinct membrane localisation is also observed in a range of tumours. IQGAP1 is a node intersected by many signaling pathways. As such it has many binding partners, many of which have essential roles in control of
5750-404: Is often enormous—as much as 10 -fold increase in rate over the uncatalysed reaction in the case of orotate decarboxylase (78 million years without the enzyme, 18 milliseconds with the enzyme). The molecules bound and acted upon by enzymes are called substrates . Although enzymes can consist of hundreds of amino acids, it is usually only a small fraction of the residues that come in contact with
5875-559: Is one which contains mutations that prevent GTP hydrolysis, thus locking Ras in a permanently 'On' state. The most common mutations are found at residue G12 in the P-loop and the catalytic residue Q61. See also "dominant negative" mutants such as S17N and D119N. Reovirus was noted to be a potential cancer therapeutic when studies suggested it reproduces well in certain cancer cell lines. It replicates specifically in cells that have an activated Ras pathway (a cellular signaling pathway that
6000-535: Is the code for methionine . Because DNA contains four nucleotides, the total number of possible codons is 64; hence, there is some redundancy in the genetic code, with some amino acids specified by more than one codon. Genes encoded in DNA are first transcribed into pre- messenger RNA (mRNA) by proteins such as RNA polymerase . Most organisms then process the pre-mRNA (also known as a primary transcript ) using various forms of post-transcriptional modification to form
6125-510: Is to integrate and mediate signaling from diverse pathways and insulate key pathway members from crosstalk . Scaffolds organize signaling pathways —help regulate how various extracellular signals can be transduced by the same canonical pathway members into various cellular outputs. Generally, scaffolds regulate output, localization, and selectivity of pathways. As a scaffold involved in different signaling pathways (actin cytoskeleton , cellular adhesion , cell cycle , transcription), IQGAP1 has
6250-479: Is usually sequestered in a complex and excluded from the nucleus, but upon WNT activation this complex is broken and beta-catenin translocates to the nucleus where it activates transcriptional programs. IQGAP1 binds b-catenin and increases nuclear localization and expression of beta-catenin’s transcriptional targets. IQGAP1 is associated with cytoskeletal dynamics, transcription, cell adhesion , cell cycle , and morphology , all of which are disrupted in cancer . As
6375-486: The actin cytoskeleton , transcription, and cellular adhesion to regulating the cell cycle . IQGAP1 was discovered in 1994. Its name stems from the fact that its RasGAP-related domain (GRD) has sequence homology to the Sar1 GTPase. It was hypothesized that IQGAP1 would act as a GTPase activating protein (GAP) protein, promoting the switch of ras GTPases from the active GTP to GDP-bound forms. However, despite
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#17327937725516500-492: The amino acid leucine for which he found a (nearly correct) molecular weight of 131 Da . Early nutritional scientists such as the German Carl von Voit believed that protein was the most important nutrient for maintaining the structure of the body, because it was generally believed that "flesh makes flesh." Around 1862, Karl Heinrich Ritthausen isolated the amino acid glutamic acid . Thomas Burr Osborne compiled
6625-410: The cell cycle , and other cellular functions. IQGAP is particularly interesting as a therapeutic target since it acts as a node for so many signaling pathways implicated in cancer progression. Analysis of IQGAP1 expression in human tissues has indicated that the scaffold is more or less ubiquitously expressed. It is usually found in the nucleus , plasma membrane , and cytoplasm . In other words it
6750-497: The mitogen-activated protein (MAP) kinase cascade has been well-studied. This cascade transmits signals downstream and results in the transcription of genes involved in cell growth and division. Another Ras-activated signaling pathway is the PI3K/AKT/mTOR pathway , which stimulates protein synthesis, cellular migration and growth, and inhibits apoptosis. Ras is a guanosine - nucleotide -binding protein. Specifically, it
6875-644: The muscle sarcomere , with a molecular mass of almost 3,000 kDa and a total length of almost 27,000 amino acids. Short proteins can also be synthesized chemically by a family of methods known as peptide synthesis , which rely on organic synthesis techniques such as chemical ligation to produce peptides in high yield. Chemical synthesis allows for the introduction of non-natural amino acids into polypeptide chains, such as attachment of fluorescent probes to amino acid side chains. These methods are useful in laboratory biochemistry and cell biology , though generally not for commercial applications. Chemical synthesis
7000-593: The plasma membrane account for its predominant localization at the cell surface at steady-state. NRAS and HRAS are further processed on the surface of the Golgi apparatus by palmitoylation of one or two Cys residues, respectively, adjacent to the CaaX box . The proteins thereby become stably membrane anchored (lipid-rafts) and are transported to the plasma membrane on vesicles of the secretory pathway . Depalmitoylation by acyl-protein thioesterases eventually releases
7125-645: The sperm of many multicellular organisms which reproduce sexually . They also generate the forces exerted by contracting muscles and play essential roles in intracellular transport. A key question in molecular biology is how proteins evolve, i.e. how can mutations (or rather changes in amino acid sequence) lead to new structures and functions? Most amino acids in a protein can be changed without disrupting activity or function, as can be seen from numerous homologous proteins across species (as collected in specialized databases for protein families , e.g. PFAM ). In order to prevent dramatic consequences of mutations,
7250-497: The 1700s by Antoine Fourcroy and others, who often collectively called them " albumins ", or "albuminous materials" ( Eiweisskörper , in German). Gluten , for example, was first separated from wheat in published research around 1747, and later determined to exist in many plants. In 1789, Antoine Fourcroy recognized three distinct varieties of animal proteins: albumin , fibrin , and gelatin . Vegetable (plant) proteins studied in
7375-572: The 1950s, the Armour Hot Dog Company purified 1 kg of pure bovine pancreatic ribonuclease A and made it freely available to scientists; this gesture helped ribonuclease A become a major target for biochemical study for the following decades. The understanding of proteins as polypeptides , or chains of amino acids, came through the work of Franz Hofmeister and Hermann Emil Fischer in 1902. The central role of proteins as enzymes in living organisms that catalyzed reactions
7500-498: The 20,000 or so proteins encoded by the human genome, only 6,000 are detected in lymphoblastoid cells. Proteins are assembled from amino acids using information encoded in genes. Each protein has its own unique amino acid sequence that is specified by the nucleotide sequence of the gene encoding this protein. The genetic code is a set of three-nucleotide sets called codons and each three-nucleotide combination designates an amino acid, for example AUG ( adenine – uracil – guanine )
7625-519: The EC number system provides a functional classification scheme. Similarly, the gene ontology classifies both genes and proteins by their biological and biochemical function, but also by their intracellular location. Sequence similarity is used to classify proteins both in terms of evolutionary and functional similarity. This may use either whole proteins or protein domains , especially in multi-domain proteins . Protein domains allow protein classification by
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#17327937725517750-419: The GDP conjugate. Mammal Ras induces meiosis in X. laevis oocytes almost certainly by potentiating insulin -induced meiosis, but not progesterone -induced. Protein synthesis does not seem to be a part of this step. Injection increases synthesis of diacylglycerol from phosphatidylcholine . Some meiosis effects are antagonized by rap1 (and by a Ras modified to dock incorrectly). Both rap1 and
7875-597: The Harvey sarcoma virus and Kirsten sarcoma virus, by Edward M. Scolnick and colleagues at the National Institutes of Health (NIH). These viruses were discovered originally in rats during the 1960s by Jennifer Harvey and Werner H. Kirsten , respectively, hence the name Ra t s arcoma . In 1982, activated and transforming human ras genes were discovered in human cancer cells by Geoffrey M. Cooper at Harvard, Mariano Barbacid and Stuart A. Aaronson at
8000-676: The NIH, Robert Weinberg at MIT, and Michael Wigler at Cold Spring Harbor Laboratory. A third ras gene was subsequently discovered by researchers in the group of Robin Weiss at the Institute of Cancer Research , and Michael Wigler at Cold Spring Harbor Laboratory, named NRAS , for its initial identification in human neuroblastoma cells. The three human ras genes encode extremely similar proteins made up of chains of 188 to 189 amino acids. Their gene symbols are HRAS , NRAS and KRAS ,
8125-501: The P-loop and magnesium cation binding site and inhibit the interaction of these with the gamma phosphate anion . Acidic (negative) residues in switch II "pull" a lysine in the P-loop away from the GDP which "pushes" switch I away from the guanine. The contacts holding GDP in place are broken and it is released into the cytoplasm. Because intracellular GTP is abundant relative to GDP (approximately 10 fold more) GTP predominantly re-enters
8250-427: The P-loop, binds the beta phosphate of GDP and GTP. The G2 motif, also called Switch I or SW1, contains threonine35, which binds the terminal phosphate (γ-phosphate) of GTP and the divalent magnesium ion bound in the active site. The G3 motif, also called Switch II or SW2, has a DXXGQ motif. The D is aspartate57, which is specific for guanine versus adenine binding, and Q is glutamine61, the crucial residue that activates
8375-544: The Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumors. It is reasonable to speculate that a pharmacological approach that curtails Ras activity may represent a possible method to inhibit certain cancer types. Ras point mutations are the single most common abnormality of human proto-oncogenes. Ras inhibitor trans-farnesylthiosalicylic acid (FTS, Salirasib ) exhibits profound anti-oncogenic effects in many cancer cell lines. Inappropriate activation of
8500-450: The Ras subfamily are HRAS , KRAS and NRAS , mainly for being implicated in many types of cancer. However, there are many other members of this subfamily as well: DIRAS1 ; DIRAS2 ; DIRAS3 ; ERAS ; GEM ; MRAS ; NKIRAS1 ; NKIRAS2 ; RALA ; RALB ; RAP1A ; RAP1B ; RAP2A ; RAP2B ; RAP2C ; RASD1 ; RASD2 ; RASL10A ; RASL10B ; RASL11A ; RASL11B ; RASL12 ; REM1 ; REM2 ; RERG ; RERGL ; RRAD ; RRAS ; RRAS2 Mutations in
8625-709: The ability of many enzymes to bind and process multiple substrates . When mutations occur, the specificity of an enzyme can increase (or decrease) and thus its enzymatic activity. Thus, bacteria (or other organisms) can adapt to different food sources, including unnatural substrates such as plastic. Methods commonly used to study protein structure and function include immunohistochemistry , site-directed mutagenesis , X-ray crystallography , nuclear magnetic resonance and mass spectrometry . The activities and structures of proteins may be examined in vitro , in vivo , and in silico . In vitro studies of purified proteins in controlled environments are useful for learning how
8750-419: The actin cytoskeleton. Despite its name, IQGAP1 does not have GAP function, and instead stabilizes active Cdc42. This increase in a local pool of active Cdc42 stimulates actin filament formation and thus filopodia formation. IQGAP1 can crosslink actin, and in many organisms, IQGAP1 is involved in cytokinesis . Cadherins are a family of adhesion proteins that localize to the cell surface where they anchor
8875-405: The addition of a single methyl group to a binding partner can sometimes suffice to nearly eliminate binding; for example, the aminoacyl tRNA synthetase specific to the amino acid valine discriminates against the very similar side chain of the amino acid isoleucine . Proteins can bind to other proteins as well as to small-molecule substrates. When proteins bind specifically to other copies of
9000-549: The alpha carbons are roughly coplanar . The other two dihedral angles in the peptide bond determine the local shape assumed by the protein backbone. The end with a free amino group is known as the N-terminus or amino terminus, whereas the end of the protein with a free carboxyl group is known as the C-terminus or carboxy terminus (the sequence of the protein is written from N-terminus to C-terminus, from left to right). The words protein , polypeptide, and peptide are
9125-531: The amino acid side chains in a protein that ultimately determines its three-dimensional structure and its chemical reactivity. The amino acids in a polypeptide chain are linked by peptide bonds . Once linked in the protein chain, an individual amino acid is called a residue, and the linked series of carbon, nitrogen, and oxygen atoms are known as the main chain or protein backbone. The peptide bond has two resonance forms that contribute some double-bond character and inhibit rotation around its axis, so that
9250-574: The binding of a substrate molecule to an enzyme's active site , or the physical region of the protein that participates in chemical catalysis. In solution, proteins also undergo variation in structure through thermal vibration and the collision with other molecules. Proteins can be informally divided into three main classes, which correlate with typical tertiary structures: globular proteins , fibrous proteins , and membrane proteins . Almost all globular proteins are soluble and many are enzymes. Fibrous proteins are often structural, such as collagen ,
9375-570: The body of a multicellular organism. These proteins must have a high binding affinity when their ligand is present in high concentrations, but must also release the ligand when it is present at low concentrations in the target tissues. The canonical example of a ligand-binding protein is haemoglobin , which transports oxygen from the lungs to other organs and tissues in all vertebrates and has close homologs in every biological kingdom . Lectins are sugar-binding proteins which are highly specific for their sugar moieties. Lectins typically play
9500-585: The brain, IQGAP3 appears to play an important role in neuronal morphogenesis. This gene encodes a member of the IQGAP family. The protein contains four IQ domains , one calponin homology domain , one Ras-GAP domain and one WW domain . It interacts with components of the cytoskeleton such as the formin Dia1 ( mDia1 ), with cell adhesion molecules ( CAMs ), and with several signaling molecules to regulate cell morphology and motility . For example, IQGAP1 expression
9625-442: The cell cycle and actin cytoskeleton. IQGAP1 has been shown to interact with: Protein binding does not by itself construct an interesting story. Far more important is the outcome of the binding event. Does binding change the target protein’s localization? Does it activate the target, or in some way change the target (or effector molecule’s) conformation? As a scaffolding protein , IQGAP1 binds and regulates many targets—its role
9750-558: The cell is as enzymes , which catalyse chemical reactions. Enzymes are usually highly specific and accelerate only one or a few chemical reactions. Enzymes carry out most of the reactions involved in metabolism , as well as manipulating DNA in processes such as DNA replication , DNA repair , and transcription . Some enzymes act on other proteins to add or remove chemical groups in a process known as posttranslational modification. About 4,000 reactions are known to be catalysed by enzymes. The rate acceleration conferred by enzymatic catalysis
9875-436: The cell surface and an effector domain within the cell, which may have enzymatic activity or may undergo a conformational change detected by other proteins within the cell. Antibodies are protein components of an adaptive immune system whose main function is to bind antigens , or foreign substances in the body, and target them for destruction. Antibodies can be secreted into the extracellular environment or anchored in
10000-752: The cell's machinery through the process of protein turnover . A protein's lifespan is measured in terms of its half-life and covers a wide range. They can exist for minutes or years with an average lifespan of 1–2 days in mammalian cells. Abnormal or misfolded proteins are degraded more rapidly either due to being targeted for destruction or due to being unstable. Like other biological macromolecules such as polysaccharides and nucleic acids , proteins are essential parts of organisms and participate in virtually every process within cells . Many proteins are enzymes that catalyse biochemical reactions and are vital to metabolism . Proteins also have structural or mechanical functions, such as actin and myosin in muscle and
10125-450: The cell. Many ion channel proteins are specialized to select for only a particular ion; for example, potassium and sodium channels often discriminate for only one of the two ions. Structural proteins confer stiffness and rigidity to otherwise-fluid biological components. Most structural proteins are fibrous proteins ; for example, collagen and elastin are critical components of connective tissue such as cartilage , and keratin
10250-621: The chemical properties of their amino acids, others require the aid of molecular chaperones to fold into their native states. Biochemists often refer to four distinct aspects of a protein's structure: Proteins are not entirely rigid molecules. In addition to these levels of structure, proteins may shift between several related structures while they perform their functions. In the context of these functional rearrangements, these tertiary or quaternary structures are usually referred to as " conformations ", and transitions between them are called conformational changes. Such changes are often induced by
10375-441: The chief actors within the cell, said to be carrying out the duties specified by the information encoded in genes. With the exception of certain types of RNA , most other biological molecules are relatively inert elements upon which proteins act. Proteins make up half the dry weight of an Escherichia coli cell, whereas other macromolecules such as DNA and RNA make up only 3% and 20%, respectively. The set of proteins expressed in
10500-474: The complex. Active RAC1 binds IQGAP1 to crosslink actin filaments and prevents IQGAP1 from interacting with beta-catenin , stabilizing cell-cell contacts . When IQGAP1 does not bind Rac1, however, it binds beta-catenin, displacing a-catenin from the cadherin-catenin cellular adhesion complex. IQGAP1 also affects transcription through the Wnt signaling pathway by its interaction with beta-catenin . Beta-catenin
10625-490: The construction of enormously complex signaling networks. As interactions between proteins are reversible, and depend heavily on the availability of different groups of partner proteins to form aggregates that are capable to carry out discrete sets of function, study of the interactions between specific proteins is a key to understand important aspects of cellular function, and ultimately the properties that distinguish particular cell types. The best-known role of proteins in
10750-408: The derivative unit kilodalton (kDa). The average size of a protein increases from Archaea to Bacteria to Eukaryote (283, 311, 438 residues and 31, 34, 49 kDa respectively) due to a bigger number of protein domains constituting proteins in higher organisms. For instance, yeast proteins are on average 466 amino acids long and 53 kDa in mass. The largest known proteins are the titins , a component of
10875-490: The domains are not always highly conserved. IQGAP1 is the most well studied member of the IQGAP family of scaffold proteins. The two other members of the family include IQGAP2 and IQGAP3 which have far more restricted expression patterns in comparison with IQGAP1. IQGAP2 is found in the liver, stomach, and platelets and is 62% identical to IQGAP1, but appears to have a drastically divergent function in terms of pathology. In
11000-451: The erroneous conclusion that they might be composed of a single type of (very large) molecule. The term "protein" to describe these molecules was proposed by Mulder's associate Berzelius; protein is derived from the Greek word πρώτειος ( proteios ), meaning "primary", "in the lead", or "standing in front", + -in . Mulder went on to identify the products of protein degradation such as
11125-416: The gene has been shown to play a key role in improper signal transduction, proliferation and malignant transformation. Mutations in a number of different genes as well as RAS itself can have this effect. Oncogenes such as p210BCR-ABL or the growth receptor erbB are upstream of Ras, so if they are constitutively activated their signals will transduce through Ras. The tumour suppressor gene NF1 encodes
11250-419: The homology of IQGAP’s GAP domain to sar1 and the fact that IQGAP1 binds Rho GTPases Rac1 and Cdc42, IQGAP does not actually have GAP function. Instead, it binds the active (GTP-bound) forms of RAC1 and CDC42 with higher affinity than GDP-bound forms, and stabilizes the active form in vivo. IQGAP1 is now recognized as a protein scaffold that integrates signals regulating cell adhesion , actin cytoskeleton,
11375-432: The inactive state of Ras family members. Other proteins that augment this cycle may exist. Ras is attached to the cell membrane owing to its prenylation and palmitoylation ( HRAS and NRAS ) or the combination of prenylation and a polybasic sequence adjacent to the prenylation site ( KRAS ). The C-terminal CaaX box of Ras first gets farnesylated at its Cys residue in the cytosol, allowing Ras to loosely insert into
11500-534: The late 1700s and early 1800s included gluten , plant albumin , gliadin , and legumin . Proteins were first described by the Dutch chemist Gerardus Johannes Mulder and named by the Swedish chemist Jöns Jacob Berzelius in 1838. Mulder carried out elemental analysis of common proteins and found that nearly all proteins had the same empirical formula , C 400 H 620 N 100 O 120 P 1 S 1 . He came to
11625-558: The latter of which produces the K-Ras4A and K-Ras4B isoforms from alternative splicing . Ras contains six beta strands and five alpha helices . It consists of two domains: a G domain of 166 amino acids (about 20 kDa) that binds guanosine nucleotides, and a C-terminal membrane targeting region (CAAX-COOH, also known as CAAX box ), which is lipid-modified by farnesyl transferase , RCE1 , and ICMT . The G domain contains five G motifs that bind GDP/GTP directly. The G1 motif, or
11750-478: The major component of connective tissue, or keratin , the protein component of hair and nails. Membrane proteins often serve as receptors or provide channels for polar or charged molecules to pass through the cell membrane . A special case of intramolecular hydrogen bonds within proteins, poorly shielded from water attack and hence promoting their own dehydration , are called dehydrons . Many proteins are composed of several protein domains , i.e. segments of
11875-443: The mature mRNA, which is then used as a template for protein synthesis by the ribosome . In prokaryotes the mRNA may either be used as soon as it is produced, or be bound by a ribosome after having moved away from the nucleoid . In contrast, eukaryotes make mRNA in the cell nucleus and then translocate it across the nuclear membrane into the cytoplasm , where protein synthesis then takes place. The rate of protein synthesis
12000-477: The membrane of the endoplasmatic reticulum and other cellular membranes. The Tripeptide (aaX) is then cleaved from the C-terminus by a specific prenyl-protein specific endoprotease and the new C-terminus is methylated by a methyltransferase . KRas processing is completed at this stage. Dynamic electrostatic interactions between its positively charged basic sequence with negative charges at the inner leaflet of
12125-405: The membranes of specialized B cells known as plasma cells . Whereas enzymes are limited in their binding affinity for their substrates by the necessity of conducting their reaction, antibodies have no such constraints. An antibody's binding affinity to its target is extraordinarily high. Many ligand transport proteins bind particular small biomolecules and transport them to other locations in
12250-479: The mice, and MCF-7 cells with stable knockdown of IQGAP1 only formed tumors 20% of the time. The mechanism for how IQGAP1 may modulate tumorigenesis/invasion through its various binding partners is of great interest. IQGAP1 null mice appear significantly normal, with the only life history abnormality being an increase in gastric hyperplasia . Thus, IQGAP1 may be an effective therapeutic target, if its knockdown has little effect in homeostatic tissue but its expression
12375-522: The modified Ras are co-antagonists with p120Ras GAP in this pathway. Expressed in all tissues of Drosophila melanogaster but mostly in neural cells. Overexpression is somewhat lethal and, during development, produces eye and wing abnormalities. (This parallels - and may be the reason for - similar abnormalities due to mutated receptor tyrosine kinases .) The D. genes for ras es in mammals produce abnormalities. Most expression in Aplysia spp.
12500-429: The most common oncogenes in human cancer; mutations that permanently activate Ras are found in 20 to 25% of all human tumors and up to 90% in certain types of cancer (e.g., pancreatic cancer ). For this reason, Ras inhibitors are being studied as a treatment for cancer and other diseases with Ras overexpression. The first two Ras genes, HRAS and KRAS , were identified from studies of two cancer-causing viruses,
12625-496: The nobel prize in 1972, solidified the thermodynamic hypothesis of protein folding, according to which the folded form of a protein represents its free energy minimum. With the development of X-ray crystallography , it became possible to determine protein structures as well as their sequences. The first protein structures to be solved were hemoglobin by Max Perutz and myoglobin by John Kendrew , in 1958. The use of computers and increasing computing power also supported
12750-713: The nucleotide binding pocket of Ras and reloads the spring. Thus GEFs facilitate Ras activation . Well known GEFs include Son of Sevenless (Sos) and cdc25 which include the RasGEF domain . The balance between GEF and GAP activity determines the guanine nucleotide status of Ras, thereby regulating Ras activity. In the GTP-bound conformation, Ras has a high affinity for numerous effectors which allow it to carry out its functions. These include PI3K . Other small GTPases may bind adaptors such as arfaptin or second messenger systems such as adenylyl cyclase . The Ras binding domain
12875-500: The order of 50,000 to 1 million. By contrast, eukaryotic cells are larger and thus contain much more protein. For instance, yeast cells have been estimated to contain about 50 million proteins and human cells on the order of 1 to 3 billion. The concentration of individual protein copies ranges from a few molecules per cell up to 20 million. Not all genes coding proteins are expressed in most cells and their number depends on, for example, cell type and external stimuli. For instance, of
13000-440: The physical and chemical properties, folding, stability, activity, and ultimately, the function of the proteins. Some proteins have non-peptide groups attached, which can be called prosthetic groups or cofactors . Proteins can also work together to achieve a particular function, and they often associate to form stable protein complexes . Once formed, proteins only exist for a certain period and are then degraded and recycled by
13125-424: The process of cell signaling and signal transduction . Some proteins, such as insulin , are extracellular proteins that transmit a signal from the cell in which they were synthesized to other cells in distant tissues . Others are membrane proteins that act as receptors whose main function is to bind a signaling molecule and induce a biochemical response in the cell. Many receptors have a binding site exposed on
13250-574: The processes of cell proliferation , differentiation , and apoptosis . This pathway is conserved across all eukaryotes . Various extracellular signals induce the ERK MAPK pathway including EGF , IGF-1 , PDGF , and NGF . The various scaffolds of this pathway, including IQGAP1, are responsible for modulating the cellular response to the activity of this pathway. For instance, in a given cell line, activation by one extracellular signal may induce differentiation but not proliferation, while activation of
13375-534: The protein or proteins of interest based on properties such as molecular weight, net charge and binding affinity. The level of purification can be monitored using various types of gel electrophoresis if the desired protein's molecular weight and isoelectric point are known, by spectroscopy if the protein has distinguishable spectroscopic features, or by enzyme assays if the protein has enzymatic activity. Additionally, proteins can be isolated according to their charge using electrofocusing . For natural proteins,
13500-402: The proteins from the membrane, allowing them to enter another cycle of palmitoylation and depalmitoylation. This cycle is believed to prevent the leakage of NRAS and HRAS to other membranes over time and to maintain their steady-state localization along the Golgi apparatus , secretory pathway , plasma membrane and inter-linked endocytosis pathway. The clinically most notable members of
13625-427: The proteins in the cytoskeleton , which form a system of scaffolding that maintains cell shape. Other proteins are important in cell signaling, immune responses , cell adhesion , and the cell cycle . In animals, proteins are needed in the diet to provide the essential amino acids that cannot be synthesized . Digestion breaks the proteins down for metabolic use. Proteins have been studied and recognized since
13750-452: The regulation of the above-mentioned localization of Ras. Farnesyltransferase inhibitors have been developed to stop the farnesylation of Ras and therefore weaken its affinity to membranes. Other inhibitors are targeting the palmitoylation cycle of Ras through inhibiting depalmitoylation by acyl-protein thioesterases , potentially leading to a destabilization of the Ras cycle. A novel inhibitor finding strategy for mutated Ras molecules
13875-446: The same ERK MAPK pathway by a different extracellular signal will induce proliferation but not differentiation. IQGAP1 seems to be responsible for the specific output of the pathway upon activation by EGF. IQGAP1 plays a significant role in the propagation of this MAPK signaling pathway. IQGAP directly binds b-RAF , MEK1/2 and ERK1/2, and is in fact necessary for the phosphorylation (activation) of ERK upon stimulation by EGF. Actin
14000-582: The same molecule, they can oligomerize to form fibrils; this process occurs often in structural proteins that consist of globular monomers that self-associate to form rigid fibers. Protein–protein interactions also regulate enzymatic activity, control progression through the cell cycle , and allow the assembly of large protein complexes that carry out many closely related reactions with a common biological function. Proteins can also bind to, or even be integrated into, cell membranes. The ability of binding partners to induce conformational changes in proteins allows
14125-581: The sample, allowing scientists to obtain more information and analyze larger structures. Computational protein structure prediction of small protein structural domains has also helped researchers to approach atomic-level resolution of protein structures. As of April 2024 , the Protein Data Bank contains 181,018 X-ray, 19,809 EM and 12,697 NMR protein structures. Proteins are primarily classified by sequence and structure, although other classifications are commonly used. Especially for enzymes
14250-430: The sequencing of complex proteins. In 1999, Roger Kornberg succeeded in sequencing the highly complex structure of RNA polymerase using high intensity X-rays from synchrotrons . Since then, cryo-electron microscopy (cryo-EM) of large macromolecular assemblies has been developed. Cryo-EM uses protein samples that are frozen rather than crystals, and beams of electrons rather than X-rays. It causes less damage to
14375-405: The substrate, and an even smaller fraction—three to four residues on average—that are directly involved in catalysis. The region of the enzyme that binds the substrate and contains the catalytic residues is known as the active site . Dirigent proteins are members of a class of proteins that dictate the stereochemistry of a compound synthesized by other enzymes. Many proteins are involved in
14500-716: The surrounding amino acids may determine the exact binding specificity). Many such motifs has been collected in the Eukaryotic Linear Motif (ELM) database. Topology of a protein describes the entanglement of the backbone and the arrangement of contacts within the folded chain. Two theoretical frameworks of knot theory and Circuit topology have been applied to characterise protein topology. Being able to describe protein topology opens up new pathways for protein engineering and pharmaceutical development, and adds to our understanding of protein misfolding diseases such as neuromuscular disorders and cancer. Proteins are
14625-400: The tRNA molecules with the correct amino acids. The growing polypeptide is often termed the nascent chain . Proteins are always biosynthesized from N-terminus to C-terminus . The size of a synthesized protein can be measured by the number of amino acids it contains and by its total molecular mass , which is normally reported in units of daltons (synonymous with atomic mass units ), or
14750-472: The tertiary structure of the protein, which defines the binding site pocket, and by the chemical properties of the surrounding amino acids' side chains. Protein binding can be extraordinarily tight and specific; for example, the ribonuclease inhibitor protein binds to human angiogenin with a sub-femtomolar dissociation constant (<10 M) but does not bind at all to its amphibian homolog onconase (> 1 M). Extremely minor chemical changes such as
14875-880: The two switch motifs is what mediates the basic functionality as a molecular switch protein. This GTP-bound state of Ras is the "on" state, and the GDP-bound state is the "off" state. The two switch motifs have a number of conformations when binding GTP or GDP or no nucleotide (when bound to SOS1, which releases the nucleotide). Ras also binds a magnesium ion which helps to coordinate nucleotide binding. Ras proteins function as binary molecular switches that control intracellular signaling networks. Ras-regulated signal pathways control such processes as actin cytoskeletal integrity, cell proliferation , cell differentiation , cell adhesion , apoptosis , and cell migration . Ras and Ras-related proteins are often deregulated in cancers, leading to increased invasion and metastasis , and decreased apoptosis. Ras activates several pathways, of which
15000-455: The two switch regions in a "loaded-spring" configuration (specifically the Thr-35 and Gly-60). When released, the switch regions relax which causes a conformational change into the inactive state. Hence, activation and deactivation of Ras and other small G proteins are controlled by cycling between the active GTP-bound and inactive GDP-bound forms. The process of exchanging the bound nucleotide
15125-472: Was insulin , by Frederick Sanger , in 1949. Sanger correctly determined the amino acid sequence of insulin, thus conclusively demonstrating that proteins consisted of linear polymers of amino acids rather than branched chains, colloids , or cyclols . He won the Nobel Prize for this achievement in 1958. Christian Anfinsen 's studies of the oxidative folding process of ribonuclease A, for which he won
15250-709: Was associated with increased migration and invasion in a human breast epithelial cancer cell line ( MCF-7 cells). IQGAP1 may also be involved in the deregulation of proliferation and differentiation through its modulation of the ERK MAPK pathway . IQGAP1 may be necessary for tumorigenesis . IQGAP1 knockdown in MCF-7 cancer cells reduced the malignant phenotype (serum-dependent proliferation and anchorage independent growth). 100% of mice injected with MCF-7 cells overexpressing IQGAP1 developed tumors and these tumors were highly invasive. Control MCF-7 cells formed tumors in 60% of
15375-406: Was described in. The Ras mutations in the 12th residue position inhibit the bound of the regulatory GAP molecule to the mutated Ras, causing uncontrolled cell growth. The novel strategy proposes finding small glue molecules, which attach the mutated Ras to the GAP, prohibiting uncontrolled cell growth and restoring the normal function. For this goal a theoretical Ras-GAP conformation was designed with
15500-581: Was not fully appreciated until 1926, when James B. Sumner showed that the enzyme urease was in fact a protein. Linus Pauling is credited with the successful prediction of regular protein secondary structures based on hydrogen bonding , an idea first put forth by William Astbury in 1933. Later work by Walter Kauzmann on denaturation , based partly on previous studies by Kaj Linderstrøm-Lang , contributed an understanding of protein folding and structure mediated by hydrophobic interactions . The first protein to have its amino acid chain sequenced
15625-460: Was thus thought to have GAP function. IQGAP1 does bind Rho GTPases CDC42 and RAC1 , however, IQGAP1 is unusual in that it actually has no GAP function, and instead stabilizes the GTP-bound proteins in their active state. Finally, IQGAP1 has a RasGAP_c carboxy terminal sequence important for binding Beta-catenin and E-cadherin . Homologues of IQGAP1 are known in species as divergent as yeast, worms, and humans (as well as other mammals), though
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