Identifiers | |||||||||
---|---|---|---|---|---|---|---|---|---|
Symbol | SH2 | ||||||||
Pfam | PF00017 | ||||||||
InterPro | IPR000980 | ||||||||
SMART | SH2 | ||||||||
PROSITE | PDOC50001 | ||||||||
SCOP2 | 1sha / SCOPe / SUPFAM | ||||||||
CDD | cd00173 | ||||||||
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The SH2 (Src Homology 2) domain is a structurally conserved protein domain contained within the Src oncoprotein [2] and in many other intracellular signal-transducing proteins. [3] SH2 domains bind to phosphorylated tyrosine residues on other proteins, modifying the function or activity of the SH2-containing protein. The SH2 domain may be considered the prototypical modular protein-protein interaction domain, allowing the transmission of signals controlling a variety of cellular functions. [4] SH2 domains are especially common in adaptor proteins that aid in the signal transduction of receptor tyrosine kinase pathways. [5]
SH2 domains contain about 100 amino acid residues and exhibit a central antiparallel β-sheet centered between two α-helices. [6] Binding to phosphotyrosine-containing peptides involves a strictly-conserved Arg residue that pairs with the negatively-charged phosphate on the phosphotyrosine, [7] and a surrounding pocket that recognizes flanking sequences on the target peptide. [6] [7] Compared to other signaling proteins, SH2 domains exhibit only a moderate degree of specificity for their target peptides, due to the relative weakness of the interactions with the flanking sequences. [8]
Over 100 human proteins are known to contain SH2 domains. [9] A variety of tyrosine-containing sequences have been found to bind SH2 domains and are conserved across a wide range of organisms, performing similar functions. [10] Binding of a phosphotyrosine-containing protein to an SH2 domain may lead to either activation or inactivation of the SH2-containing protein, depending on the types of interactions formed between the SH2 domain and other domains of the enzyme. Mutations that disrupt the structural stability of the SH2 domain, or that affect the binding of the phosphotyrosine peptide of the target, are involved in a range of diseases including X-linked agammaglobulinemia and severe combined immunodeficiency. [11]
SH2 domains are not present in yeast and appear at the boundary between protozoa and animalia in organisms such as the social amoeba Dictyostelium discoideum . [12]
A detailed bioinformatic examination of SH2 domains of human and mouse reveals 120 SH2 domains contained within 115 proteins encoded by the human genome, [13] representing a rapid rate of evolutionary expansion among the SH2 domains.
A large number of SH2 domain structures have been solved and many SH2 proteins have been knocked out in mice.
SH2 domains, and other binding domains, have been used in protein engineering to create protein assemblies. Protein assemblies are formed when several proteins bind to one another to create a larger structure (called a supramolecular assembly). Using molecular biology techniques, fusion proteins of specific enzymes and SH2 domains have been created, which can bind to each other to form protein assemblies.
Since SH2 domains require phosphorylation in order for binding to occur, the use of kinase and phosphatase enzymes gives researchers control over whether protein assemblies will form or not. High affinity engineered SH2 domains have been developed and utilized for protein assembly applications. [14]
The goal of most protein assembly formation is to increase the efficiency of metabolic pathways via enzymatic co-localization. [15] Other applications of SH2 domain mediated protein assemblies have been in the formation of high density fractal-like structures, which have extensive molecular trapping properties. [16]
Human proteins containing this domain include:
The SRC Homology 3 Domain is a small protein domain of about 60 amino acid residues. Initially, SH3 was described as a conserved sequence in the viral adaptor protein v-Crk. This domain is also present in the molecules of phospholipase and several cytoplasmic tyrosine kinases such as Abl and Src. It has also been identified in several other protein families such as: PI3 Kinase, Ras GTPase-activating protein, CDC24 and cdc25. SH3 domains are found in proteins of signaling pathways regulating the cytoskeleton, the Ras protein, and the Src kinase and many others. The SH3 proteins interact with adaptor proteins and tyrosine kinases. Interacting with tyrosine kinases, SH3 proteins usually bind far away from the active site. Approximately 300 SH3 domains are found in proteins encoded in the human genome. In addition to that, the SH3 domain was responsible for controlling protein-protein interactions in the signal transduction pathways and regulating the interactions of proteins involved in the cytoplasmic signaling.
The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeostasis; a functional process that under degenerate conditions may result in a range of clinical manifestations including diabetes and cancer. Insulin signalling controls access to blood glucose in body cells. When insulin falls, especially in those with high insulin sensitivity, body cells begin only to have access to lipids that do not require transport across the membrane. So, in this way, insulin is the key regulator of fat metabolism as well. Biochemically, the insulin receptor is encoded by a single gene INSR, from which alternate splicing during transcription results in either IR-A or IR-B isoforms. Downstream post-translational events of either isoform result in the formation of a proteolytically cleaved α and β subunit, which upon combination are ultimately capable of homo or hetero-dimerisation to produce the ≈320 kDa disulfide-linked transmembrane insulin receptor.
The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumor formation. The pathway communicates information from chemical signals outside of a cell to the cell nucleus, resulting in the activation of genes through the process of transcription. There are three key parts of JAK-STAT signalling: Janus kinases (JAKs), signal transducer and activator of transcription proteins (STATs), and receptors. Disrupted JAK-STAT signalling may lead to a variety of diseases, such as skin conditions, cancers, and disorders affecting the immune system.
Tyrosin-protein kinase Lck is a 56 kDa protein that is found inside lymphocytes and encoded in the human by the LCK gene. The Lck is a member of Src kinase family (SFK) and is important for the activation of T-cell receptor (TCR) signaling in both naive T cells and effector T cells. The role of Lck is less prominent in the activation or in the maintenance of memory CD8 T cells in comparison to CD4 T cells. In addition, the constitutive activity of the mouse Lck homolog varies among memory T cell subsets. It seems that in mice, in the effector memory T cell (TEM) population, more than 50% of Lck is present in a constitutively active conformation, whereas less than 20% of Lck is present as active form in central memory T cells. These differences are due to differential regulation by SH2 domain–containing phosphatase-1 (Shp-1) and C-terminal Src kinase.
Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. The receptors are generally activated by dimerization and substrate presentation. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.
Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular differentiation, cell growth, development and many diseases including cancer. There are two forms of the PDGF-R, alpha and beta each encoded by a different gene. Depending on which growth factor is bound, PDGF-R homo- or heterodimerizes.
Growth factor receptor-bound protein 2, also known as Grb2, is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene.
Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase (PTP) Shp2.
ZAP-70 is a protein normally expressed near the surface membrane of lymphocytes. It is most prominently known to be recruited upon antigen binding to the T cell receptor (TCR), and it plays a critical role in T cell signaling.
The breakpoint cluster region protein (BCR) also known as renal carcinoma antigen NY-REN-26 is a protein that in humans is encoded by the BCR gene. BCR is one of the two genes in the BCR-ABL fusion protein, which is associated with the Philadelphia chromosome. Two transcript variants encoding different isoforms have been found for this gene.
GRB2-associated-binding protein 2 also known as GAB2 is a protein that in humans is encoded by the GAB2 gene.
SHC-transforming protein 1 is a protein that in humans is encoded by the SHC1 gene. SHC has been found to be important in the regulation of apoptosis and drug resistance in mammalian cells.
RAS p21 protein activator 1 or RasGAP, also known as RASA1, is a 120-kDa cytosolic human protein that provides two principal activities:
Src homology 2 (SH2) domain containing inositol polyphosphate 5-phosphatase 1(SHIP1) is an enzyme with phosphatase activity. SHIP1 is structured by multiple domain and is encoded by the INPP5D gene in humans. SHIP1 is expressed predominantly by hematopoietic cells but also, for example, by osteoblasts and endothelial cells. This phosphatase is important for the regulation of cellular activation. Not only catalytic but also adaptor activities of this protein are involved in this process. Its movement from the cytosol to the cytoplasmic membrane, where predominantly performs its function, is mediated by tyrosine phosphorylation of the intracellular chains of cell surface receptors that SHIP1 binds. Insufficient regulation of SHIP1 leads to different pathologies.
SH2 domain-containing adapter protein B is a protein that in humans is encoded by the SHB gene.
Ankyrin repeat and SAM domain-containing protein 1A (ANKS1A), also known as ODIN, is a protein that in humans is encoded by the ANKS1A gene on chromosome 6.
A non-receptor tyrosine kinase (nRTK) is a cytosolic enzyme that is responsible for catalysing the transfer of a phosphate group from a nucleoside triphosphate donor, such as ATP, to tyrosine residues in proteins. Non-receptor tyrosine kinases are a subgroup of protein family tyrosine kinases, enzymes that can transfer the phosphate group from ATP to a tyrosine residue of a protein (phosphorylation). These enzymes regulate many cellular functions by switching on or switching off other enzymes in a cell.
Src kinase family is a family of non-receptor tyrosine kinases that includes nine members: Src, Yes, Fyn, and Fgr, forming the SrcA subfamily, Lck, Hck, Blk, and Lyn in the SrcB subfamily, and Frk in its own subfamily. Frk has homologs in invertebrates such as flies and worms, and Src homologs exist in organisms as diverse as unicellular choanoflagellates, but the SrcA and SrcB subfamilies are specific to vertebrates. Src family kinases contain six conserved domains: a N-terminal myristoylated segment, a SH2 domain, a SH3 domain, a linker region, a tyrosine kinase domain, and C-terminal tail.
Autophosphorylation is a type of post-translational modification of proteins. It is generally defined as the phosphorylation of the kinase by itself. In eukaryotes, this process occurs by the addition of a phosphate group to serine, threonine or tyrosine residues within protein kinases, normally to regulate the catalytic activity. Autophosphorylation may occur when a kinases' own active site catalyzes the phosphorylation reaction, or when another kinase of the same type provides the active site that carries out the chemistry. The latter often occurs when kinase molecules dimerize. In general, the phosphate groups introduced are gamma phosphates from nucleoside triphosphates, most commonly ATP.
Tyrosine-protein kinase CSK also known as C-terminal Src kinase is an enzyme that, in humans, is encoded by the CSK gene. This enzyme phosphorylates tyrosine residues located in the C-terminal end of Src-family kinases (SFKs) including SRC, HCK, FYN, LCK, LYN and YES1.