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847  structures 549  species 0  interactions 59304  sequences 1043  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]

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 adaptor proteins that aid in the signal transduction of receptor tyrosine kinase pathways.[4]


SH2 is conserved by signalization of protein tyrosine kinase, which are binding on phosphotyrosine (pTyr).[5] In the human proteome the class of pTyr-selective recognition domains is represented by SH2 domains. The N-terminal SH2 domains of cytoplasmic tyrosine kinase was at the beginning of evolution evolved with the occurrence of tyrosine phosphorylation. At the beginning it was supposed that, these domains serve as a substrate for their target kinase.[6]

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.[7] 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.[8][9]

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


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.[11]

A detailed bioinformatic examination of SH2 domains of human and mouse reveals 120 SH2 domains contained within 115 proteins encoded by the human genome,[12] 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.


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.


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.[13]

The goal of most protein assembly formation is to increase the efficiency of metabolic pathways via enzymatic co-localization.[14] 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.[15]


Human proteins containing this domain include:

See also


  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". Journal of Molecular Biology. 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". Molecular and Cellular Biology. 6 (12): 4396–408. doi:10.1128/mcb.6.12.4396. 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 Letters. 304 (1): 15–20. doi:10.1016/0014-5793(92)80579-6. PMID 1377638. S2CID 7046771.
  4. ^ Koytiger G, Kaushansky A, Gordus A, Rush J, Sorger PK, MacBeath G (May 2013). "Phosphotyrosine signaling proteins that drive oncogenesis tend to be highly interconnected". Molecular & Cellular Proteomics. 12 (5): 1204–13. doi:10.1074/mcp.M112.025858. PMC 3650332. PMID 23358503.
  5. ^ Chervitz SA, Aravind L, Sherlock G, Ball CA, Koonin EV, Dwight SS, Harris MA, Dolinski K, Mohr S, Smith T, Weng S, Cherry JM, Botstein D (December 1998). "Comparison of the complete protein sets of worm and yeast: orthology and divergence". Science. 282 (5396): 2022–8. doi:10.1126/science.282.5396.2022. PMC 3057080. PMID 9851918.
  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. ^ Liu BA, Shah E, Jablonowski K, Stergachis A, Engelmann B, Nash PD (December 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. PMC 4255630. PMID 22155787.
  8. ^ 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.
  9. ^ 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. doi:10.1074/mcp.M700312-MCP200. PMID 17956856.
  10. ^ Ren S, Yang G, He Y, Wang Y, Li Y, Chen Z (October 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.
  11. ^ Eichinger L, Pachebat JA, Glöckner G, Rajandream MA, Sucgang R, Berriman M, 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.
  12. ^ 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.
  13. ^ Kaneko, T.; Huang, H.; Cao, X.; Li, X.; Li, C.; Voss, C.; Sidhu, S. S.; Li, S. S. C. (2012-09-25). "Superbinder SH2 Domains Act as Antagonists of Cell Signaling". Science Signaling. 5 (243): ra68. doi:10.1126/scisignal.2003021. ISSN 1945-0877. PMID 23012655. S2CID 28562514.
  14. ^ Yang, Lu; Dolan, E.M.; Tan, S.K.; Lin, T.; Sontag, E.D.; Khare, S.D. (2017). "Computation-Guided Design of a Stimulus-Responsive Multienzyme Supramolecular Assembly". ChemBioChem. 18 (20): 2000–2006. doi:10.1002/cbic.201700425. ISSN 1439-7633. PMID 28799209. S2CID 13339534.
  15. ^ Hernández N.E., Hansen W.A., Zhu D., Shea M.E., Khalid M., Manichev V., Putnins M., Chen M., Dodge A.G., Yang L., Marrero-Berríos I., Banal M., Rechani P., Gustafsson T., Feldman L.C., Lee S-.H., Wackett L.P., Dai W., Khare S.D. (2019). Stimulus-responsive self-assembly of protein-based fractals by computational design. Nat. Chem. 2019 11(7): 605-614. Pre-print available at bioRxiv doi: 10.1101/274183.

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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 ].

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 4 members:

Cbl_N3 MelC1 SH2 SH2_2


We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...

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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...


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.

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Seed source: Swissprot_feature_table
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: Sonnhammer ELL
Number in seed: 52
Number in full: 59304
Average length of the domain: 78.50 aa
Average identity of full alignment: 28 %
Average coverage of the sequence by the domain: 13.73 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 21.0 21.0
Trusted cut-off 21.0 21.0
Noise cut-off 20.9 20.9
Model length: 77
Family (HMM) version: 27
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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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 847 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 sequence.

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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A061ADQ6 View 3D Structure Click here
A0A096MKD7 View 3D Structure Click here
A0A0B4LHY5 View 3D Structure Click here
A0A0G2JUA7 View 3D Structure Click here
A0A0G2JX93 View 3D Structure Click here
A0A0G2JYH7 View 3D Structure Click here
A0A0G2K134 View 3D Structure Click here
A0A0G2K9S1 View 3D Structure Click here
A0A0G2KA94 View 3D Structure Click here
A0A0G2L1J5 View 3D Structure Click here
A0A0G2L4Z6 View 3D Structure Click here
A0A0H2UKT8 View 3D Structure Click here
A0A0R4I9L1 View 3D Structure Click here
A0A0R4IAA4 View 3D Structure Click here
A0A0R4IFZ8 View 3D Structure Click here
A0A0R4IKB3 View 3D Structure Click here
A0A0R4IUJ2 View 3D Structure Click here
A0A0R4IVP7 View 3D Structure Click here
A0A0R4IYB8 View 3D Structure Click here
A0A0R4J755 View 3D Structure Click here
A0A0R4J8U1 View 3D Structure Click here
A0A0S4FT70 View 3D Structure Click here
A0A286Y8A3 View 3D Structure Click here
A0A286Y8W8 View 3D Structure Click here
A0A286Y960 View 3D Structure Click here
A0A2R8PV98 View 3D Structure Click here
A0A2R8Q0N0 View 3D Structure Click here
A0A2R8Q2G2 View 3D Structure Click here
A0A2R8Q2T0 View 3D Structure Click here
A0A2R8Q7T0 View 3D Structure Click here
A0A2R8Q947 View 3D Structure Click here
A0A2R8QBA3 View 3D Structure Click here
A0A2R8QC59 View 3D Structure Click here
A0A2R8QG88 View 3D Structure Click here
A0A2R8QIU7 View 3D Structure Click here
A0A2R8QL35 View 3D Structure Click here
A0A2R8QNV0 View 3D Structure Click here
A0A2R8QR19 View 3D Structure Click here
A0A2R8RIA7 View 3D Structure Click here
A0A2R8RLP1 View 3D Structure Click here