SH2 domain

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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
OPM protein 1xa6

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]

Contents

[edit] Introduction

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 115 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.

[edit] 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.[4][5]

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

[edit] Diversity

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.[6]

A detailed bioinformatic examination of SH2 domains of human and mouse reveals 120 SH2 domains contained within 115 proteins encoded by the human genome,[7] 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.[8]

[edit] Function

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.

[edit] Examples

Human proteins containing this domain include:

[edit] References

  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. PMID 3025655. PMC 367222. http://mcb.asm.org/cgi/pmidlookup?view=long&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. PMID 1377638. http://linkinghub.elsevier.com/retrieve/pii/0014-5793(92)80579-6. 
  4. ^ Pawson T, Gish GD, Nash P (December 2001). "[h 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. h. 
  5. ^ 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. 
  6. ^ 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. PMID 15875012. 
  7. ^ 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. 
  8. ^ Nash P, Pawson T, Jablonowski K. "the SH2 domain". The University of Chicago. http://sh2.uchicago.edu/. Retrieved 2008-11-08. 

[edit] External links

v • d • e
Protein tertiary structure
General
All-α folds:
All-β folds:
α/β folds:
α+β folds:
DNA clamp · Ferredoxin fold · Ribonuclease A · SH2-like fold
Irregular folds:
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