| SH3 domain | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 Ribbon diagram of the SH3 domain, alpha spectrin, fromchicken (PDB accession code 1SHG), colored from blue (N-terminus) to red (C-terminus). | |||||||||
| Identifiers | |||||||||
| Symbol | SH3_1 | ||||||||
| Pfam | PF00018 | ||||||||
| Pfam clan | CL0010 | ||||||||
| ECOD | 4.1.1 | ||||||||
| InterPro | IPR001452 | ||||||||
| SMART | SM00326 | ||||||||
| PROSITE | PS50002 | ||||||||
| SCOP2 | 1shf /SCOPe /SUPFAM | ||||||||
| CDD | cd00174 | ||||||||
| |||||||||
TheSRC Homology 3 Domain (orSH3 domain) is a smallprotein domain of about 60amino acid residues. Initially, SH3 was described as aconserved sequence in theviraladaptor protein v-Crk. This domain is also present in the molecules of phospholipase and several cytoplasmictyrosine kinases such asAbl andSrc.[1][2] It has also been identified in several other protein families such as:PI3 Kinase,RasGTPase-activating protein,CDC24 andcdc25.[3][4][5] SH3 domains are found in proteins of signaling pathways regulating thecytoskeleton, theRas protein, and theSrc 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 theactive 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 thesignal transduction pathways[6] and regulating the interactions of proteins involved in the cytoplasmic signaling.[7]
The SH3 domain has a characteristicbeta-barrel fold that consists of five or sixβ-strands arranged as two tightly packedanti-parallel β sheets. The linker regions may contain short helices. The SH3-type fold is an ancient fold found in eukaryotes as well as prokaryotes.[8]
The classical SH3 domain is usually found in proteins that interact with otherproteins and mediate assembly of specific protein complexes, typically via binding toproline-richpeptides in their respective binding partner. Classical SH3 domains are restricted in humans to intracellular proteins, although the small human MIA family of extracellular proteins also contain a domain with an SH3-like fold.
Many SH3-binding epitopes of proteins have aconsensus sequence that can be represented as a regular expression orShort linear motif:
-X-P-p-X-P- 1 2 3 4 5
with 1 and 4 beingaliphatic amino acids, 2 and 5 always and 3 sometimes being proline. The sequence binds to thehydrophobic pocket of the SH3 domain. More recently, SH3 domains that bind to a core consensus motif R-x-x-K have been described. Examples are the C-terminal SH3 domains of adaptor proteins like Grb2 and Mona (a.k.a. Gads, Grap2, Grf40, GrpL etc.). Other SH3 binding motifs have emerged and are still emerging in the course of various molecular studies, highlighting the versatility of this domain.
SH3 domain-mediated protein-protein interaction networks,i.e., SH3 interactomes, revealed that worm SH3 interactome resembles the analogous yeast network because it is significantly enriched for proteins with roles in endocytosis.[9][10] Nevertheless, orthologous SH3 domain-mediated interactions are highly rewired between worm and yeast.[9]