54209
88-518: 83433 ENSG00000095970 ENSMUSG00000023992 Q9NZC2 Q99NH8 NM_001271821 NM_018965 NM_001272078 NM_031254 NP_001258750 NP_061838 NP_001259007 NP_112544 Triggering receptor expressed on myeloid cells 2 (TREM2) is a protein that in humans is encoded by the TREM2 gene . TREM2 is expressed on macrophages, immature monocyte-derived dendritic cells , osteoclasts , and microglia , which are immune cells in
176-520: 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
264-470: 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.
352-552: 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,
440-403: 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
528-851: 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
616-478: 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
704-410: 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
792-500: 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
880-411: 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
968-542: 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
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#17327648447141056-486: 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
1144-406: 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 "),
1232-791: A soluble version, called soluble TREM2 ( sTREM2 ). This protein fragment is released into the serum and cerebral spinal fluid ( CSF ), and might serve as a biomarker for neurodegenerative and other disorders, but further studies are needed. The TREM2 protein is found in immune cells termed myeloid cells , which include macrophages , granulocytes , monocytes, and dendritic cells. Monocyte-, macrophage-, and neutrophil -mediated inflammatory responses can be stimulated through G protein -linked 7-transmembrane receptors (e.g., FPR1 ), Fc receptors , CD14 , toll like receptors (such as TLR4 ), and cytokine receptors (e.g., IFNGR1 ). Engagement of these receptors can also prime myeloid cells to respond to other stimuli. Myeloid cells express receptors belonging to
1320-432: 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
1408-441: 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
1496-558: Is a young cell of the granulocytic series, occurring normally in bone marrow (can be found in circulating blood when caused by certain diseases). When stained with the usual dyes, the cytoplasm is distinctly basophilic and relatively more abundant than in myeloblasts or promyelocytes , even though myelocytes are smaller cells. Numerous cytoplasmic granules are present in the more mature forms of myelocytes. Neutrophilic and eosinophilic granules are peroxidase -positive, while basophilic granules are not. The nuclear chromatin
1584-408: 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. Myelocyte A myelocyte
1672-548: Is believed to negatively regulate TREM2 signaling by acting as decoy receptors. sTREM might therefore have pro-inflammatory effects. sTREM2 has been indicated in activating signaling pathways such as PI3K and ERK through an unidentified receptor. Levels of sTREM2 are increased in CSF of patients with Alzheimer's disease , and correlate with the CSF levels of disease biomarkers, such as t-tau and p-tau. TREM2 signaling has been associated with pathogenesis of several diseases. Variants of in
1760-562: 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
1848-628: 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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#17327648447141936-469: 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"
2024-461: 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
2112-576: Is likely to have distinct roles in the pathogenesis of these disorders, so therapeutic agents in development employ different approaches to modify TREM2 activity. In the brain, TREM2 is expressed on microglia that regulate clearance of neuronal debris. Binding of apolipoproteins , such as ApoE, to TREM2 promotes phagocytosis of apoptotic neurons or the uptake of amyloid beta by microglia. Variants of TREM2 that encode proteins with reduced affinity for ligands have been associated with Alzheimer’s disease. A potential mechanism of intervention could be targeting
2200-404: 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
2288-501: Is reduced following inflammatory signaling induction by lipopolysaccharide (a TLR4 ligand) or interferon gamma ( IFNG ). The neuroprotective effects of TREM2 involve not only production of anti-inflammatory cytokines, but also clearance of abnormal proteins and phagocytosis of apoptotic neurons. In contrast to anti-inflammatory effects in brain and cancer, TREM2 signaling has been reported to contribute to intestinal inflammation and development of inflammatory bowel diseases (IBD) . sTREM2
2376-535: 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
2464-467: The DAP12 (TYROBP) or TREM2 genes have been associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL or Nasu–Hakola disease). Variants of TREM2 have been associated with neurodegenerative disorders, including Alzheimer's disease . TREM2 is involved in the microglial response to the amyloid plaques that are characteristic of AD. Loss of TREM2 function reduces
2552-420: The TREM2 mRNA transcript leads to different isoforms of the protein being produced upon translation. Specifically, TREM2 mRNA has 3 different isoforms containing 3 consistent exons, and 2 that vary between the isoforms. TREM2 mRNA is most highly expressed in brain, lungs, adrenal glands , placenta , gall bladder , and colon. The functions of TREM2 have been studied in mice with disruption or mutation of
2640-492: 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
2728-518: The central nervous system . In the liver , TREM2 is expressed by several cell types, including macrophages, that respond to injury. In the intestine , TREM2 is expressed by myeloid-derived dendritic cells and macrophage. TREM2 is overexpressed in many tumor types and has anti-inflammatory activities. It might therefore be a good therapeutic target . The TREM2 gene lies on the sixth chromosome in humans, specifically in location 6p21.1. The gene has 5 coding exon regions. Alternative splicing of
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2816-594: The immunoglobulin (Ig) superfamily , such as TREM2, or to the C-type lectin superfamily. On myeloid cells, TREM2 binds anionic molecules, free and bound to plasma membrane, including bacterial products, DNA, lipoproteins , phospholipids , glycoproteins, DNA, and bacterial fragments. TREM2 binding of ligand results in phosphorylation at 2 tyrosines in the immunoreceptor tyrosine-based activation motif (ITAM) of DAP12 by SRC tyrosine kinases. Spleen tyrosine kinase ( Syk ) interacts with these phosphorylation sites and activates
2904-644: 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
2992-568: The phosphatidylinositol-3 kinase ( PI3K ) signaling pathway, as well as other signaling molecules such as mTOR , MAPK , and ERK . Association of TREM2 with DAP10 also activates the PI3K signaling pathway, leading to expression of transcription factors that include AP1 , NF-κB , and NFAT . The PI3K signaling pathway also increases intracellular calcium content, which activates calcium-dependent kinases. TREM2 activation also affects expression of GAL1 , GAL3 , IL1RN , and progranulin , which modulate
3080-645: 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,
3168-517: The spinal cord , and levels of TREM2 increase with age in humans and mice. TREM2 is also expressed by macrophages of adipose tissue , adrenal gland, and placenta. Immunosuppressive tumor-associated macrophages ( TAMs ) have been characterized by expression of TREM2. TREM2 signaling leads to downregulated transcription of genes that promote inflammation ( Tnf, Il1b, and Nos2 ), as well as release of cytokines that prevent activation of anti-tumor CD8 T cells . TREM2 immunosuppressive TAMs correlate with
3256-497: 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
3344-572: 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
3432-498: 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 )
3520-519: 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
3608-709: 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
TREM2 - Misplaced Pages Continue
3696-405: 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
3784-607: 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
3872-531: 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
3960-475: The area of insult. TREM2 appears to reduce the inflammatory response induced by TLR signaling and promote microglial migration, survival, and regeneration. TREM2 has also been linked to additional disorders such as ALS , Parkinson's disease , and more dementia related conditions. TREM2 is a good therapeutic target for several diseases, including cancer and liver and neurodegenerative diseases. Several companies are developing agents to target TREM2. However, TREM2
4048-574: 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 ,
4136-570: 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
4224-558: 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
4312-436: 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
4400-752: 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
4488-450: 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
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#17327648447144576-621: 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
4664-441: 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
4752-490: 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
4840-408: 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
4928-761: The enzymes that cleave the ectodomain, adjusting the rate at which sTREM2 is released. In rodents, a potential therapeutic using this mechanism was used against AD pathology, and the rodents had smaller plaques than controls. 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
5016-451: 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
5104-406: The immune response. TREM2 is expressed by microglia and osteoclasts, and is involved in development and/or maintenance of brain and bone. In mice, TREM2 is involved in synaptic pruning , a process of shaping neuronal circuitry by microglia- and astrocyte-mediated removal of excessive synapses via phagocytosis . In brain, the highest levels of TREM2 are found in hippocampus , white matter , and
5192-421: The intestine. Expression of TREM2 is limited to inflamed sections of intestine and contribute to IBD development. TREM2 is associated with increased production of inflammatory cytokines and changes in the gut microbiota. One feature of liver disease is the initiation of an inflammatory process, leading to fibrosis and steatohepatitis . In mouse models of nonalcoholic steatohepatitis (NASH), disease development
5280-534: 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
5368-411: The level of exhausted T cells in the human tumor microenvironment ( TME ). A TREM2 TAM-rich TME therefore appears to be immune suppressive and might promote resistance to cancer therapies, such as checkpoint inhibitors . TREM2 signaling can antagonize TLR expression and signaling, resulting in reduced production of inflammatory cytokines by cultured mouse macrophages. Conversely, TREM2 expression
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#17327648447145456-577: The main cell type in the brain that is affected is the microglia, where TREM2 is expressed. Several recessive, inactivating mutations in TREM2 and TYROBP (encodes DAP12 protein) have been identified that can cause PLOSL. The mutations prevent association between TREM2 and DAP12 or expression of shorter, non-functional forms of TREM2. Loss of function of TREM2 signaling increases the inflammatory responses of microglia, reducing clearance of dead neurons and promoting inflammation and even formation of amyloid plaques. During ischemic stroke , microglia respond to
5544-478: 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
5632-443: 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
5720-405: 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
5808-532: The mouse ortholog, Trem2 . TREM2 orthologs are also present in rat, dog, Rhesus monkey, macaque, chimpanzee, and other animals. The TREM2 receptor is a transmembrane protein that is made up of an extracellular region (also referred to as the ectodomain), the membrane-traversing segment , and an intracellular component. The extracellular component of TREM2 can bind different anionic ligands, specifically glycoproteins and lipids . This ectodomain component includes an Ig-like V-type domain , where ligands bind
5896-496: 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
5984-500: 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
6072-440: 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
6160-424: 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
6248-534: 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,
6336-427: 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
6424-531: The receptor. The TREM2 ectodomain is modified after protein translation; these modifications affect its affinity for different ligands. The intracellular component of TREM2 does not have any signaling ability on its own; rather, it signals via the DNAX activator proteins 10 and 12 ( DAP10 and DAP12 ). A single TREM2 molecule can interact with DAP10 and DAP12 at the same time. Part of the ectodomain of TREM2 can be processed by enzymes ( ADAM10 , ADAM17 ) and released as
6512-455: The resolution of inflammation during hepatic injury, ultimately preventing parenchymal cell death. PLOSL or Nasu–Hakola disease is a neurodegenerative disorder characterized by bone cysts, dementia, and early death and is associated with variants in the TYROBP gene (encodes DAP12 protein) and TREM2 gene. Bone cysts in patients with PLOSL contain fat in lieu of bone marrow. In this disease,
6600-473: The responses of microglia to plaques, which then appear to take on a more toxic state. Expression of TREM2 is associated with that of CD33 . Zhong et al. reported that, in mice, stereotactic injection of sTREM2 or adeno-associated virus-mediated activation of sTREM2 reduced the amyloid plaque load and reduced functional memory deficits . Moreover, sTREM2 stimulated microglial proliferation and homing toward amyloid plaques where amyloid-β uptake and degradation
6688-582: 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
6776-581: 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
6864-430: 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
6952-405: 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
7040-716: 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
7128-400: 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
7216-472: 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
7304-472: 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
7392-442: Was also increased in liver tissues from patients with cirrhosis. Compared with non-tumor liver tissue, TREM2 expression was increased in tumors from mice and patients with hepatocellular carcinoma (HCC). This study also showed that disruption of Trem2 promoted tumor development and exacerbated liver damage and inflammation. In liver tumors, TREM2 was expressed by tumor-infiltrating macrophages (TAMs). TREM2 might therefore promote
7480-463: Was associated with liver infiltration by monocyte-derived macrophages and increased expression of Trem2 and Cd9 . Mice with disruption of Trem2 had more severe liver damage following administration of carbon tetrachloride or acetaminophen , compared to mice without gene disruption. The authors of this study found that TREM2 is expressed by Kupfer cells and hepatic stellate cells , indicating that TREM2 might downregulate inflammation. Expression
7568-463: Was associated with shorter survival times of patients with ovarian cancer , gastric cancer , lower-grade glioma , hepatocellular carcinoma , or renal clear cell carcinoma . Tumor infiltration by TREM2, APOE , C1q macrophage was reported to be a biomarker for recurrence of clear-cell renal carcinoma . TREM2 macrophages from human tumors also express CD68 , CD163 , CSF1R , and nuclear MAFB . TREM2 expressed by human monocyte dendritic cells in
7656-694: Was increased. Interestingly, these effects were specifically mediated by microglia. Level of sTREM2 in the CSF might be a biomarker for Alzheimer's disease and the associated inflammatory response. Although TREM2 expression is low in most normal tissues, it is overexpressed in many human tumor types. An analysis of levels of TREM2 mRNA in 33 cancer tissues from The Cancer Genome Atlas (TCGA) indicate higher levels of expression in tumor vs normal tissues in 18 cancer types, including head and neck squamous cell carcinoma , colon adenocarcinoma , and glioblastoma , as well as gynecologic, liver, gastric, kidney, breast, bladder, and esophageal cancers. High expression of TREM2
7744-581: 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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