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390  structures 283  species 8  interactions 9081  sequences 379  architectures

Family: SH2 (PF00017)

Summary: SH2 domain

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SH2 domain Edit Wikipedia article

1lkkA SH2 domain.png
Crystallographic structure of the SH2 domain. The structure consists of a large beta sheet (green) flanked by two alpha-helices (orange and blue).[1]
Identifiers
Symbol SH2
Pfam PF00017
InterPro IPR000980
SMART SH2
PROSITE PDOC50001
SCOP 1sha
SUPERFAMILY 1sha
OPM protein 1xa6
CDD cd00173

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 allow proteins containing those domains to dock to phosphorylated tyrosine residues on other proteins. SH2 domains are commonly found in adapter proteins that aid in the signal transduction of receptor tyrosine kinase pathways.[4]

Introduction[edit]

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.[5] 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[edit]

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.[6][7]

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. [8] The intimate relationship between tyrosine kinases and SH2 domains is supported by their coordinate emergence during eukaryotic evolution.

Diversity[edit]

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.[9]

A detailed bioinformatic examination of SH2 domains of human and mouse reveals 120 SH2 domains contained within 115 proteins encoded by the human genome,[10] 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.[11]

Function[edit]

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.

Examples[edit]

Human proteins containing this domain include:

References[edit]

  1. ^ PDB 1lkk; 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. doi:10.1006/jmbi.1996.0112. PMID 8604142. 
  2. ^ 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 367222. PMID 3025655. 
  3. ^ 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. doi:10.1016/0014-5793(92)80579-6. PMID 1377638. 
  4. ^ 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. doi:10.1074/mcp.M112.025858. PMID 23358503. 
  5. ^ 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. doi:10.1126/scisignal.2002105. PMID 22155787.  edit
  6. ^ Pawson T, Gish GD, Nash P (December 2001). "SH2 domains, interaction modules and cellular wiring". Trends in Cell Biology 11 (12): 504–11. doi:10.1016/S0962-8924(01)02154-7. PMID 11719057. 
  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 : MCP 7 (4): 768–84. doi:10.1074/mcp.M700312-MCP200. PMID 17956856. 
  8. ^ 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. doi:10.1186/1471-2164-9-452. PMC 2576256. PMID 18828911.  edit
  9. ^ Eichinger L, Pachebat JA, Glöckner G, et al. (May 2005). "The genome of the social amoeba Dictyostelium discoideum". Nature 435 (7038): 43–57. doi:10.1038/nature03481. PMC 1352341. PMID 15875012. 
  10. ^ 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. doi:10.1016/j.molcel.2006.06.001. PMID 16793553. 
  11. ^ Nash P, Pawson T, Jablonowski K. "the SH2 domain". The University of Chicago. Retrieved 2008-11-08. 

External links[edit]

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Internal database links

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].

Gene Ontology

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Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan SH2-like (CL0541), which has the following description:

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

Alignments

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  Seed
(58)
Full
(9081)
Representative proteomes NCBI
(8244)
Meta
(21)
RP15
(1219)
RP35
(1597)
RP55
(2956)
RP75
(4864)
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  Seed
(58)
Full
(9081)
Representative proteomes NCBI
(8244)
Meta
(21)
RP15
(1219)
RP35
(1597)
RP55
(2956)
RP75
(4864)
Alignment:
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  Seed
(58)
Full
(9081)
Representative proteomes NCBI
(8244)
Meta
(21)
RP15
(1219)
RP35
(1597)
RP55
(2956)
RP75
(4864)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Swissprot_feature_table
Previous IDs: none
Type: Domain
Author: Sonnhammer ELL
Number in seed: 58
Number in full: 9081
Average length of the domain: 78.00 aa
Average identity of full alignment: 27 %
Average coverage of the sequence by the domain: 14.81 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.9 20.9
Trusted cut-off 20.9 20.9
Noise cut-off 20.8 20.8
Model length: 77
Family (HMM) version: 19
Download: download the raw HMM for this family

Species distribution

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Interactions

There are 8 interactions for this family. More...

Y_phosphatase SH3_2 STAT_bind SH3_1 Pkinase_Tyr C1_1 SH2 SOCS_box

Structures

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 390 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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