SH3 Domain
Class:Pro-rich Binding
Structure:

No Image The basic fold of SH3 domains contains five anti-parallel beta-strands packed to form two perpendicular beta-sheets. The ligand-binding site consists of a hydrophobic patch that contains a cluster of conserved aromatic residues and is surrounded by two charged and variable loops. The figure shows a Sem5 C-terminal SH3 domain complexed to the mSos-derived sequence PPPVGPRRR.

Structure Reference:
Nguyen, JT. et al. (1998) Science. 282(5396): 2088-92. PDB: 3SEM.
 

Domain binding and function:
Src-homology 3 (SH3) domains generally bind to Pro-rich peptides that form a left-handed polyPro type II helix, with the minimal consensus Pro-X-X-Pro. Each Pro is usually preceded by an aliphatic residue. Each of these aliphatic-Pro pairs binds to a hydrophobic pocket on the SH3 domain. The detailed requirements of SH3 domain binding to its ligand have been examined by numerous approaches including phage display combinatorial peptide chemistry, nuclear magnetic resonance and crystal structure analysis. From this, two classes of SH3 domains have been defined (Class I and Class 2) which recognize RKXXPXXP and PXXPXR motifs respecitvely. The ligand can, in principle, bind in either orientation. Directionality is conferred by the interaction of the Arg or Lys residue with the charged outer face of the SH3 domain while the tandem prolines bind within two hydrophobic pockets of the SH3 domain. An additional non-Pro residue, frequently Arg, can form part of the binding core and contacts the SH3 domain. Such peptides usually bind to the SH3 domain with Kds in the uM range. The binding affinity and specificity can be markedly increased by tertiary interactions involving loops on the SH3 domain. In a few proteins, SH3 domains have been observed to bind in an unconventional non-PXXP manner. In these cases, either an alpha helical element or a tandem tyrosine motif interacts with a site on the SH3 domain that is either distinct or overlapping with the classical PXXP binding cleft.
Examples of Proteins: 
SH3 domain protein
 Binding partner SH3 Domain Binding Site
Src tyrosine kinase p85 subunit of PI 3-kinase RPLPVAP Class I N-terminal to C-terminal binding sit
Crk adaptor protein C3G guanidine nucleotide exchanger PPPALPPKKR Class II C-terminal to N-terminal binding site
FYB (FYN binding protein) SKAP55 Adaptor protein RKGDYASY unconventional
Pex13p (integral peroxisomal membrane protein) Pex5p - PTS1 receptor WXXQF unconventional








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Referenced in part on Cell Signaling Technology Website, Reference Section on Protein Domains. We gratefully acknowledge the following contributors: Piers Nash1, Dan Lin3, Kathleen Binns2, Clark Wells2, Rob Ingham2, Terry Kubiseski2, Bernard Liu1, Matt Smith2,3, Ivan Blasutig2,3, Maria Sierra1, Caesar Lim2,3, Michael Arc1, Jim Fawcett2 and Tony Pawson2,3.
1. Ben May Institute for Cancer Research, The University of Chicago, Chicago, Illinois, 60637, USA
2. Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada
3. Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada