2M0Q
94-447: 9992 246133 ENSG00000159197 ENSMUSG00000039672 Q9Y6J6 Q9D808 NM_172201 NM_005136 NM_134110 NM_001358372 NP_751951 NP_598871 NP_001345301 Potassium voltage-gated channel subfamily E member 2 (KCNE2), also known as MinK-related peptide 1 (MiRP1), is a protein that in humans is encoded by the KCNE2 gene on chromosome 21 . MiRP1
188-520: 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
282-470: 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.
376-483: A BLAST search strategy, focusing on KCNE1 sequence stretches known to be important for function, to identify related expressed sequence tags (ESTs) in the NCBI database. Using sequences from these ESTs, KCNE2, 3 and 4 were cloned. KCNE2 protein is most readily detected in the choroid plexus epithelium, gastric parietal cells , and thyroid epithelial cells . KCNE2 is also expressed in atrial and ventricular cardiomyocytes,
470-609: A QT-prolonging agent such as sevoflurane . This is because KCNE2 is a promiscuous regulatory subunit that forms complexes with Kv1.5 and with Kv4.2 in adult mouse ventricular myocytes. KCNE2 increases currents though Kv4.2 channels and slows their inactivation. KCNE2 is required for Kv1.5 to localize to the intercalated discs of mouse ventricular myocytes. Kcne2 deletion in mice reduces the native currents generated in ventricular myocytes by Kv4.2 and Kv1.5, namely I to and I Kslow , respectively. Kcne2 -/- mice exhibit achlorhydria , gastric hyperplasia , and mis-trafficking of KCNQ1 to
564-478: A central pore that opens to allow ions to pass through. There are many different subunits available that can come together in a wide variety of combinations to form different subtypes of the ion channel. Sometimes the channel can be made from only one type of subunit, such as the α7 nicotinic receptor , which is made up from five α7 subunits, and so is a homomer rather than a heteromer, but more commonly several different types of subunit will come together to form
658-552: 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,
752-403: 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
846-851: 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
940-974: A heteromer. The ligand binding properties and intracellular trafficking pathways of GPCR heteromers usually show elements from both parent receptors, but may also produce quite unexpected pharmacological effects, making such heteromers an important focus of current research. See also [ edit ] GPCR oligomer References [ edit ] ^ Medical dictionary ^ Merriam-Webster Dictionary ^ Gotti C, Moretti M, Gaimarri A, Zanardi A, Clementi F, Zoli M (October 2007). "Heterogeneity and complexity of native brain nicotinic receptors". Biochemical Pharmacology . 74 (8): 1102–11. doi : 10.1016/j.bcp.2007.05.023 . PMID 17597586 . ^ Millar NS, Gotti C (January 2009). "Diversity of vertebrate nicotinic acetylcholine receptors" . Neuropharmacology . 56 (1): 237–46. doi : 10.1016/j.neuropharm.2008.07.041 . PMID 18723036 . S2CID 27181755 . Archived from
1034-530: A heteromeric complex (e.g., the α4β2 nicotinic receptor , which is made up from two α4 subunits and three β2 subunits). Because the different ion channel subtypes are expressed to different extents in different tissues, this allows selective modulation of ion transport and means that a single neurotransmitter can produce varying effects depending on where in the body it is released. G protein-coupled receptors are composed of seven membrane-spanning alpha-helical segments that are usually linked together into
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#17327808094341128-514: A link between myo -inositol and the seizure susceptibility and behavioral alterations in Kcne2 -/- mice. KCNE2 is also highly expressed in parietal cells of the gastric epithelium , also at the apical side. In these cells, KCNQ1 -KCNE2 K channels, which are constitutively active, provide a conduit to return K ions back to the stomach lumen. The K ions enter the parietal cell through the gastric H/K-ATPase, which swaps them for protons as it acidifies
1222-478: 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
1316-410: 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
1410-500: 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
1504-411: 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
1598-542: 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
1692-718: A range of structurally diverse pharmacological agents. This property means that many drugs or potential drugs have the capacity to impair human ventricular repolarization, leading to drug-induced long QT syndrome . KCNE2 may also regulate hyperpolarization-activated, cyclic-nucleotide-gated (HCN) pacemaker channels in human heart and in the hearts of other species, as well as the Cav1.2 voltage-gated calcium channel. In mice, mERG and KCNQ1, another Kv α subunit regulated by KCNE2, are neither influential nor highly expressed in adult ventricles. However, Kcne2 -/- mice exhibit QT prolongation at baseline at 7 months of age, or earlier if provoked with
1786-486: 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
1880-406: 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 "),
1974-772: A single folded chain to form the receptor complex. However, research has demonstrated that a number of GPCRs are also capable of forming heteromers from a combination of two or more individual GPCR subunits under some circumstances, especially where several different GPCRs are densely expressed in the same neuron. Such heteromers may be between receptors from the same family (e.g., adenosine A 1 / A 2A heteromers and dopamine D 1 /D 2 and D 1 / D 3 heteromers ) or between entirely unrelated receptors such as CB 1 /A 2A , glutamate mGluR 5 / adenosine A 2A heteromers, cannabinoid CB 1 / dopamine D 2 heteromers, and even CB 1 /A 2A /D 2 heterotrimers where three different receptors have come together to form
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#17327808094342068-485: A single membrane-spanning region, extracellular N-terminal and intracellular C-terminal . KCNE proteins have been widely studied for their roles in the heart and in genetic predisposition to inherited cardiac arrhythmias . The KCNE2 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease . More recently, roles for KCNE proteins in a variety of non-cardiac tissues have also been explored. Steve Goldstein (then at Yale University) used
2162-432: 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
2256-451: 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
2350-441: 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
2444-432: 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 is dictated by the nucleotide sequence of their genes , and which usually results in protein folding into
2538-415: Is a voltage-gated potassium channel accessory subunit (beta subunit) associated with Long QT syndrome . It is ubiquitously expressed in many tissues and cell types. Because of this and its ability to regulate multiple different ion channels , KCNE2 exerts considerable influence on a number of cell types and tissues. Human KCNE2 is a member of the five-strong family of human KCNE genes. KCNE proteins contain
2632-683: Is also associated with familial atrial fibrillation, which may involve excessive KCNQ1-KCNE2 current caused by KCNE2 gain-of-function mutations. Recently, a battery of extracardiac effects were discovered in Kcne2 -/- mice that may contribute to cardiac arrhythmogenesis in Kcne2 -/- mice and could potentially contribute to human cardiac arrhythmias if similar effects are observed in human populations. Kcne2 deletion in mice causes anemia, glucose intolerance, dyslipidemia, hyperkalemia and elevated serum angiotensin II. Some or all of these might contribute to predisposition to sudden cardiac death in Kcne2 -/- mice in
2726-427: Is also observed in sites of gastritis cystica profunda and gastric adenocarcinoma . Positron emission tomography data show that with KCNE2, 124I uptake by the thyroid is impaired. Kcne2 deletion does not impair organification of iodide once it has been taken up by NIS. Pups raised by Kcne2 -/- dams are particularly severely affected becauset they receive less milk (hypothyroidism of the dams impairs milk ejection),
2820-410: 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. Heteromer From Misplaced Pages,
2914-628: 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
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3008-469: 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"
3102-461: 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
3196-404: 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
3290-480: Is required for optimal iodide uptake into the thyroid by the basolateral sodium iodide symporter (NIS). Iodide is required for biosynthesis of thyroid hormones . KCNE2 was originally discovered to regulate hERG channel function. KCNE2 decreases macroscopic and unitary current through hERG, and speeds hERG deactivation. hERG generates IKr, the most prominent repolarizing current in human ventricular cardiomyocytes . hERG, and IKr, are highly susceptible to block by
3384-535: 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
3478-492: 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
3572-644: 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
3666-645: 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,
3760-497: 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
3854-572: 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
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3948-498: 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 )
4042-519: 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
4136-709: 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
4230-405: 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
4324-873: The adult C57 mouse as assessed with in situ hybridization" . Neuroscience . 150 (2): 370–85. doi : 10.1016/j.neuroscience.2007.09.008 . PMC 2292345 . PMID 17950542 . ^ Ciruela F, Casadó V, Rodrigues RJ, Luján R, Burgueño J, Canals M, Borycz J, Rebola N, Goldberg SR, Mallol J, Cortés A, Canela EI, López-Giménez JF, Milligan G, Lluis C, Cunha RA, Ferré S, Franco R (February 2006). "Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers" . Journal of Neuroscience . 26 (7): 2080–7. doi : 10.1523/JNEUROSCI.3574-05.2006 . PMC 6674939 . PMID 16481441 . ^ Ferre S, Ciruela F, Borycz J, Solinas M, Quarta D, Antoniou K, Quiroz C, Justinova Z, Lluis C, Franco R, Goldberg SR (2008). "Adenosine A1-A2A receptor heteromers: new targets for caffeine in
4418-607: 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
4512-531: 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
4606-625: The apical side. KCNE2 forms complexes there with the voltage-gated potassium channel α subunit, Kv1.3 . In addition, KCNE2 forms reciprocally regulating tripartite complexes in the choroid plexus epithelium with the KCNQ1 α subunit and the sodium-dependent myo -inositol transporter, SMIT1 . Kcne2 -/- mice exhibit increased seizure susceptibility, reduced immobility time in the tail suspension test, and reduced cerebrospinal fluid myo -inositol content, compared to wild-type littermates. Mega-dosing of myo -inositol reverses all these phenotypes, suggesting
4700-574: 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 ,
4794-570: 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
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#17327808094344888-1531: The brain" . Frontiers in Bioscience . 13 (13): 2391–9. doi : 10.2741/2852 . PMID 17981720 . ^ Rashid AJ, So CH, Kong MM, Furtak T, El-Ghundi M, Cheng R, O'Dowd BF, George SR (January 2007). "D1–D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum" . Proceedings of the National Academy of Sciences of the United States of America . 104 (2): 654–9. Bibcode : 2007PNAS..104..654R . doi : 10.1073/pnas.0604049104 . PMC 1766439 . PMID 17194762 . ^ Marcellino D, Ferré S, Casadó V, Cortés A, Le Foll B, Mazzola C, Drago F, Saur O, Stark H, Soriano A, Barnes C, Goldberg SR, Lluis C, Fuxe K, Franco R (September 2008). "Identification of Dopamine D1–D3 Receptor Heteromers: INDICATIONS FOR A ROLE OF SYNERGISTIC D1–D3 RECEPTOR INTERACTIONS IN THE STRIATUM" . The Journal of Biological Chemistry . 283 (38): 26016–25. doi : 10.1074/jbc.M710349200 . PMC 2533781 . PMID 18644790 . ^ Carriba P, Ortiz O, Patkar K, Justinova Z, Stroik J, Themann A, Müller C, Woods AS, Hope BT, Ciruela F, Casadó V, Canela EI, Lluis C, Goldberg SR, Moratalla R, Franco R, Ferré S (2007). "Striatal adenosine A2A and cannabinoid CB1 receptors form functional heteromeric complexes that mediate
4982-558: 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
5076-436: 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
5170-752: 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
5264-450: 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
5358-621: 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
5452-441: 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
5546-490: 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
5640-869: The context of myocardial ischemia and post-ischemic arrhythmogenesis. A multi-locus genetic risk score study based on a combination of 27 loci, including the KCNE2 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22). Protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues . Proteins perform
5734-408: 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
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#17327808094345828-451: 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
5922-455: The forebrain: relevance for schizophrenia" . Journal of Neural Transmission . 116 (8): 923–39. doi : 10.1007/s00702-008-0174-9 . PMC 2953764 . PMID 19156349 . ^ Ferré S, Baler R, Bouvier M, Caron MG, Devi LA, Durroux T, Fuxe K, George SR, Javitch JA, Lohse MJ, Mackie K, Milligan G, Pfleger KD, Pin JP, Volkow ND, Waldhoer M, Woods AS, Franco R (March 2009). "Building
6016-497: The 💕 A heteromer is something that consists of different parts; the antonym of homomeric . Examples are: Biology [ edit ] Spinal neurons that pass over to the opposite side of the spinal cord. A protein complex that contains two or more different polypeptides. Pharmacology [ edit ] Ligand-gated ion channels such as the nicotinic acetylcholine receptor and GABA A receptor are composed of five subunits arranged around
6110-448: The influence of maternal genotype in this case. As observed for hERG mutations, KCNE2 loss-of-function mutations are associated with inherited long QT syndrome, and hERG-KCNE2 channels carrying the mutations show reduced activity compared to wild-type channels. In addition, some KCNE2 mutations and also more common polymorphisms are associated with drug-induced long QT syndrome. In several cases, specific KCNE2 sequence variants increase
6204-534: 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
6298-478: 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
6392-443: 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
6486-405: 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
6580-404: The milk they receive is deficient in T 4 , and they themselves cannot adequately transport iodide into the thyroid. Kcne2 -/- pups exhibit stunted growth, alopecia , cardiomegaly and reduced cardiac ejection fraction , all of which are alleviated by thyroid hormone supplementation of pups or dams. Surrogating Kcne2 -/- pups with Kcne2 +/+ dams also alleviates these phenotypes, highlighting
6674-1270: The motor effects of cannabinoids" . Neuropsychopharmacology . 32 (11): 2249–59. doi : 10.1038/sj.npp.1301375 . PMID 17356572 . ^ Zezula J, Freissmuth M (March 2008). "The A2A-adenosine receptor: a GPCR with unique features?" . British Journal of Pharmacology . 153 Suppl 1 (S1): S184–90. doi : 10.1038/sj.bjp.0707674 . PMC 2268059 . PMID 18246094 . ^ Marcellino D, Carriba P, Filip M, Borgkvist A, Frankowska M, Bellido I, Tanganelli S, Müller CE, Fisone G, Lluis C, Agnati LF, Franco R, Fuxe K (April 2008). "Antagonistic cannabinoid CB1/dopamine D2 receptor interactions in striatal CB1/D2 heteromers. A combined neurochemical and behavioral analysis". Neuropharmacology . 54 (5): 815–23. doi : 10.1016/j.neuropharm.2007.12.011 . PMID 18262573 . S2CID 195685369 . ^ Carriba P, Navarro G, Ciruela F, Ferré S, Casadó V, Agnati L, Cortés A, Mallol J, Fuxe K, Canela EI, Lluis C, Franco R (2008). "Detection of heteromerization of more than two proteins by sequential BRET-FRET". Nature Methods . 5 (8): 727–33. doi : 10.1038/nmeth.1229 . PMID 18587404 . S2CID 5175118 . ^ Ferré S, Goldberg SR, Lluis C, Franco R (2009). "Looking for
6768-496: 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
6862-500: 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
6956-1126: The original on 2021-12-20 . Retrieved 2019-12-11 . ^ Collins AC, Salminen O, Marks MJ, Whiteaker P, Grady SR (2009). "The road to discovery of neuronal nicotinic cholinergic receptor subtypes". Nicotine Psychopharmacology . Handbook of Experimental Pharmacology. Vol. 192. pp. 85–112. doi : 10.1007/978-3-540-69248-5_4 . ISBN 978-3-540-69246-1 . PMC 8759235 . PMID 19184647 . ^ Graham AJ, Martin-Ruiz CM, Teaktong T, Ray MA, Court JA (August 2002). "Human brain nicotinic receptors, their distribution and participation in neuropsychiatric disorders". Current Drug Targets. CNS and Neurological Disorders . 1 (4): 387–97. doi : 10.2174/1568007023339283 . PMID 12769611 . ^ Nutt D (April 2006). "GABAA receptors: subtypes, regional distribution, and function" . Journal of Clinical Sleep Medicine . 2 (2): S7–11. doi : 10.5664/jcsm.26525 . PMID 17557501 . ^ Heldt SA, Ressler KJ (December 2007). "Forebrain and midbrain distribution of major benzodiazepine–sensitive GABAA receptor subunits in
7050-426: The pancreas, pituitary gland, and lung epithelium. In situ hybridization data suggest that KCNE2 transcript may also be expressed in various neuronal populations. The KCNE2 gene resides on chromosome 21 at the band 21q22.11 and contains 2 exons . Since human KCNE2 is located ~79 kb from KCNE1 and in the opposite direction, KCNE2 is proposed to originate from a gene duplication event. This protein belongs to
7144-597: The parietal cell basal membrane. The mis-trafficking occurs because KCNE3 is upregulated in the parietal cells of Kcne2 -/- mice, and hijacks KCNQ1, taking it to the basolateral membrane . When both Kcne2 and Kcne3 are germline-deleted in mice, KCNQ1 traffics to the parietal cell apical membrane but the gastric phenotype is even worse than for Kcne2 -/- mice, emphasizing that KCNQ1 requires KCNE2 co-assembly for functional attributes other than targeting in parietal cells. Kcne2 -/- mice also develop gastritis cystica profunda and gastric neoplasia . Human KCNE2 downregulation
7238-440: 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
7332-526: The potassium channel KCNE family and is one five single transmembrane domain voltage-gated potassium (Kv) channel ancillary subunits. KCNE2 is composed of three major domains: the N-terminal domain, the transmembrane domain, and the C-terminal domain. The N-terminal domain protrudes out of the extracellular side of the cell membrane and is, thus, soluble in the aqueous environment. Meanwhile,
7426-424: 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
7520-534: 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,
7614-427: 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
7708-1558: The role of cannabinoid receptor heteromers in striatal function" . Neuropharmacology . 56 (Suppl 1): 226–34. doi : 10.1016/j.neuropharm.2008.06.076 . PMC 2635338 . PMID 18691604 . ^ Franco R, Casadó V, Cortés A, Mallol J, Ciruela F, Ferré S, Lluis C, Canela EI (March 2008). "G-protein-coupled receptor heteromers: function and ligand pharmacology" . British Journal of Pharmacology . 153 Suppl 1 (S1): S90–8. doi : 10.1038/sj.bjp.0707571 . PMC 2268068 . PMID 18037920 . ^ Fuxe K, Marcellino D, Rivera A, Diaz-Cabiale Z, Filip M, Gago B, Roberts DC, Langel U, Genedani S, Ferraro L, de la Calle A, Narvaez J, Tanganelli S, Woods A, Agnati LF (August 2008). "Receptor-receptor interactions within receptor mosaics. Impact on neuropsychopharmacology". Brain Research Reviews . 58 (2): 415–52. doi : 10.1016/j.brainresrev.2007.11.007 . PMID 18222544 . S2CID 206344737 . ^ Franco R, Casadó V, Cortés A, Pérez-Capote K, Mallol J, Canela E, Ferré S, Lluis C (August 2008). "Novel pharmacological targets based on receptor heteromers". Brain Research Reviews . 58 (2): 475–82. doi : 10.1016/j.brainresrev.2008.06.002 . PMID 18620000 . S2CID 41153163 . ^ Fuxe K, Marcellino D, Woods AS, Giuseppina L, Antonelli T, Ferraro L, Tanganelli S, Agnati LF (January 2009). "Integrated signaling in heterodimers and receptor mosaics of different types of GPCRs of
7802-582: 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
7896-581: 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
7990-430: 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
8084-425: The stomach. While KCNQ1 channels are inhibited by low extracellular pH, KCNQ1-KCNE2 channels activity is augmented by extracellular protons, an ideal characteristic for their role in parietal cells. KCNE2 forms constitutively active K channels with KCNQ1 in the basolateral membrane of thyroid epithelial cells. Kcne2 -/- mice exhibit hypothyroidism , particularly apparent during gestation or lactation . KCNQ1-KCNE2
8178-405: 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
8272-716: 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
8366-546: The susceptibility to hERG-KCNE2 channel inhibition by the drug that precipitated the QT prolongation in the patient from which the gene variant was isolated. Long QT syndrome predisposes to potentially lethal ventricular cardiac arrhythmias including torsades de pointe , which can degenerate into ventricular fibrillation and sudden cardiac death . Moreover, KCNE2 gene variation can disrupt HCN1-KCNE2 channel function and this may potentially contribute to cardiac arrhythmogenesis. KCNE2
8460-400: 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
8554-472: 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
8648-473: The transmembrane and C-terminal domains are lipid-soluble to enable the protein to incorporate into the cell membrane. The C-terminal faces the intracellular side of the membrane and may share a putative PKC phosphorylation site with other KCNE proteins. Like other KCNEs, KCNE2 forms a heteromeric complex with the Kv α subunits. KCNE2 protein is most readily detected in the choroid plexus epithelium, at
8742-472: 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
8836-581: 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
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