Summary: SH2 domain
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SH2 domain Edit Wikipedia article
The SH2 (Src Homology 2) domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins. SH2 domains allow proteins containing those domains to dock to phosphorylated tyrosine residues on other proteins. SH2 domains are commonly found in adaptor proteins that aid in the signal transduction of receptor tyrosine kinase pathways.
Protein-protein interactions play a major role in cellular growth and development. Modular domains, which are the subunits of a protein, moderate these protein interactions by identifying short peptide sequences. These peptide sequences determine the binding partners of each protein. One of the more prominent domains is the SH2 domain. SH2 domains play a vital role in cellular communication. Its length is approximately 100 amino acids long and it is found within 111 human proteins. Regarding its structure, it contains 2 alpha helices and 7 beta strands. Research has shown that it has a high affinity to phosphorylated tyrosine residues and it is known to identify a sequence of 3-6 amino acids within a peptide motif.
Binding and phosphorylation
SH2 domains typically bind a phosphorylated tyrosine residue in the context of a longer peptide motif within a target protein, and SH2 domains represent the largest class of known pTyr-recognition domains.
Phosphorylation of tyrosine residues in a protein occurs during signal transduction and is carried out by tyrosine kinases. In this way, phosphorylation of a substrate by tyrosine kinases acts as a switch to trigger binding to an SH2 domain-containing protein. Many tyrosine containing short linear motifs that bind to SH2 domains are conserved across a wide variety of higher Eukaryotes. The intimate relationship between tyrosine kinases and SH2 domains is supported by their coordinate emergence during eukaryotic evolution.
A detailed bioinformatic examination of SH2 domains of human and mouse reveals 120 SH2 domains contained within 115 proteins encoded by the human genome, 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. Information generated on the Mouse Knockouts can be found on the sh2.uchicago.edu website.
The function of SH2 domains is to specifically recognize the phosphorylated state of tyrosine residues, thereby allowing SH2 domain-containing proteins to localize to tyrosine-phosphorylated sites. This process constitutes the fundamental event of signal transduction through a membrane, in which a signal in the extracellular compartment is "sensed" by a receptor and is converted in the intracellular compartment to a different chemical form, i.e. that of a phosphorylated tyrosine. Tyrosine phosphorylation leads to activation of a cascade of protein-protein interactions whereby SH2 domain-containing proteins are recruited to tyrosine-phosphorylated sites. This process initiates a series of events which eventually result in altered patterns of gene expression or other cellular responses. The SH2 domain, which was first identified in the oncoproteins Src and Fps, is about 100 amino-acid residues long. It functions as a regulatory module of intracellular signaling cascades by interacting with high affinity to phosphotyrosine-containing target peptides in a sequence-specific and strictly phosphorylation-dependent manner.
Human proteins containing this domain include:
- ABL1; ABL2
- BCAR3; BLK; BLNK; BMX; BTK
- CHN2; CISH; CRK; CRKL; CSK
- FER; FES; FGR; FRK; FYN
- GRAP; GRAP2; GRB10; GRB14; GRB2; GRB7
- HCK; HSH2D
- INPP5D; INPPL1; ITK; JAK2; LCK; LCP2; LYN
- MATK; NCK1; NCK2
- PIK3R1; PIK3R2; PIK3R3; PLCG1; PLCG2; PTK6; PTPN11; PTPN6; RASA1
- SH2B1; SH2B2; SH2B3; SH2D1A; SH2D1B; SH2D2A; SH2D3A; SH2D3C; SH2D4A; SH2D4B; SH2D5; SH2D6; SH3BP2; SHB; SHC1; SHC3; SHC4; SHD; SHE
- SLA; SLA2
- SOCS1; SOCS2; SOCS3; SOCS4; SOCS5; SOCS6; SOCS7
- SRC; SRMS
- STAT1; STAT2; STAT3; STAT4; STAT5A; STAT5B; STAT6
- SUPT6H; SYK
- TEC; TENC1; TNS; TNS1; TNS3; TNS4; TXK
- VAV1; VAV2; VAV3
- YES1; ZAP70
- Phosphotyrosine-binding domains also bind phosphorylated tyrosines
- PMID 8604142. doi:10.1006/jmbi.1996.0112.; Tong L; Warren TC; King J; Betageri R; Rose J; Jakes S (March 1996). "Crystal structures of the human p56lck SH2 domain in complex with two short phosphotyrosyl peptides at 1.0 A and 1.8 A resolution". J. Mol. Biol. 256 (3): 601–10.
- Sadowski I; Stone JC; Pawson T (December 1986). "A noncatalytic domain conserved among cytoplasmic protein-tyrosine kinases modifies the kinase function and transforming activity of Fujinami sarcoma virus P130gag-fps". Mol. Cell. Biol. 6 (12): 4396–408. PMC . PMID 3025655.
- Russell RB; Breed J; Barton GJ (June 1992). "Conservation analysis and structure prediction of the SH2 family of phosphotyrosine binding domains". FEBS Lett. 304 (1): 15–20. PMID 1377638. doi:10.1016/0014-5793(92)80579-6.
- Koytiger G; Kaushansky A; Gordus A; Rush J; Sorger PK; Macbeath G (January 2013). "Phosphotyrosine signaling proteins that drive oncogenesis tend to be highly interconnected". Mol. Cell Proteomics. 12: 1204–1213. PMID 23358503. doi:10.1074/mcp.M112.025858.
- Liu, B. A.; Shah, E.; Jablonowski, K.; Stergachis, A.; Engelmann, B.; Nash, P. D. (2011). "The SH2 Domain-Containing Proteins in 21 Species Establish the Provenance and Scope of Phosphotyrosine Signaling in Eukaryotes". Science Signaling. 4 (202): ra83. PMC . PMID 22155787. doi:10.1126/scisignal.2002105.
- Pawson T; Gish GD; Nash P (December 2001). "SH2 domains, interaction modules and cellular wiring". Trends in Cell Biology. 11 (12): 504–11. PMID 11719057. doi:10.1016/S0962-8924(01)02154-7.
- Huang H; Li L; Wu C; Schibli D; Colwill K; Ma S; Li C; Roy P; Ho K; Songyang Z; Pawson T; Gao Y; Li SS (April 2008). "Defining the specificity space of the human SRC homology 2 domain". Molecular & Cellular Proteomics. 7 (4): 768–84. PMID 17956856. doi:10.1074/mcp.M700312-MCP200.
- Ren, S.; Yang, G.; He, Y.; Wang, Y.; Li, Y.; Chen, Z. (2008). "The conservation pattern of short linear motifs is highly correlated with the function of interacting protein domains". BMC Genomics. 9: 452. PMC . PMID 18828911. doi:10.1186/1471-2164-9-452.
- Eichinger L, Pachebat JA, Glöckner G, et al. (May 2005). "The genome of the social amoeba Dictyostelium discoideum". Nature. 435 (7038): 43–57. PMC . PMID 15875012. doi:10.1038/nature03481.
- Liu BA; Jablonowski K; Raina M; Arcé M; Pawson T; Nash PD (June 2006). "The human and mouse complement of SH2 domain proteins-establishing the boundaries of phosphotyrosine signaling". Molecular Cell. 22 (6): 851–68. PMID 16793553. doi:10.1016/j.molcel.2006.06.001.
- Nash P; Pawson T; Jablonowski K. "the SH2 domain". The University of Chicago. Retrieved 2008-11-08.
- Eukaryotic Linear Motif resource motif class LIG_SH2_GRB2
- Eukaryotic Linear Motif resource motif class LIG_SH2_PTP2
- Eukaryotic Linear Motif resource motif class LIG_SH2_SRC
- Eukaryotic Linear Motif resource motif class LIG_SH2_STAT3
- Eukaryotic Linear Motif resource motif class LIG_SH2_STAT5
- Eukaryotic Linear Motif resource motif class LIG_SH2_STAT6
- Eukaryotic Linear Motif resource motif class MOD_TYR_ITAM
- Eukaryotic Linear Motif resource motif class MOD_TYR_ITIM
- Eukaryotic Linear Motif resource motif class MOD_TYR_ITSM
- Li S (2007). "SMALI site". University of Western Ontario. Retrieved 2009-01-08.
- Mayer BJ (2007-10-23). "SH2 Domain Database link page". University of Connecticut. Archived from the original on July 7, 2009. Retrieved 2009-01-08.
- The Nash Lab (2005). "the SH2 domain". The Nash Lab. Retrieved 2012-12-13.
- The Pawson Lab. "SH2 Domain". Mount Sinai Hospital, Ontario, Canada. Retrieved 2009-01-08.
- Rose T; Waksman G (2000-02-29). "SH2 domains: Introduction and Overview". Washington University School of Medicine. Retrieved 2009-01-08.
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Internal database links
|Similarity to PfamA using HHSearch:||SH2_2 SH2_2|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR000980
The Src homology 2 (SH2) domain is a protein domain of about 100 amino-acid residues first identified as a conserved sequence region between the oncoproteins Src and Fps [PUBMED:3025655]. Similar sequences were later found in many other intracellular signal-transducing proteins [PUBMED:1377638]. SH2 domains function as regulatory modules of intracellular signalling cascades by interacting with high affinity to phosphotyrosine-containing target peptides in a sequence-specific, SH2 domains recognise between 3-6 residues C-terminal to the phosphorylated tyrosine in a fashion that differs from one SH2 domain to another, and strictly phosphorylation-dependent manner [PUBMED:7883800, PUBMED:15335710, PUBMED:14731533, PUBMED:7531822]. They are found in a wide variety of protein contexts e.g., in association with catalytic domains of phospholipase Cy (PLCy) and the non-receptor protein tyrosine kinases; within structural proteins such as fodrin and tensin; and in a group of small adaptor molecules, i.e Crk and Nck. The domains are frequently found as repeats in a single protein sequence and will then often bind both mono- and di-phosphorylated substrates.
The structure of the SH2 domain belongs to the alpha+beta class, its overall shape forming a compact flattened hemisphere. The core structural elements comprise a central hydrophobic anti-parallel beta-sheet, flanked by 2 short alpha-helices. The loop between strands 2 and 3 provides many of the binding interactions with the phosphate group of its phosphopeptide ligand, and is hence designated the phosphate binding loop, the phosphorylated ligand binds perpendicular to the beta-sheet and typically interacts with the phosphate binding loop and a hydrophobic binding pocket that interacts with a pY+3 side chain. The N- and C-termini of the domain are close together in space and on the opposite face from the phosphopeptide binding surface and it has been speculated that this has facilitated their integration into surface-exposed regions of host proteins [PUBMED:11911873].
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This superfamily is characterised by proteins with the SH2-like fold. The proesence of this domain guides signal-transduction towards the phosphorylated tyrosine residues on its interacting protein-partner.
The clan contains the following 2 members:SH2 SH2_2
We make a range of alignments for each Pfam-A family:
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Curation and family details
|Number in seed:||52|
|Number in full:||15699|
|Average length of the domain:||77.60 aa|
|Average identity of full alignment:||28 %|
|Average coverage of the sequence by the domain:||14.81 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||23|
|Download:||download the raw HMM for this family|
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There are 18 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the SH2 domain has been found. There are 602 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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