SRC homology 3 domains: multifaceted binding modules

The assembly of complexes following the detection of extracellular signals is often controlled by signaling proteins comprising multiple peptide binding modules. The SRC homology (SH)3 family represents the archetypical modular protein interaction module, with ~300 annotated SH3 domains in humans th...

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Bibliographic Details
Published in:Trends in biochemical sciences (Amsterdam. Regular ed.) 2022-09, Vol.47 (9), p.772-784
Main Authors: Dionne, Ugo, Percival, Lily J., Chartier, François J.M., Landry, Christian R., Bisson, Nicolas
Format: Article
Language:English
Subjects:
liquid–liquid phase separation
phosphorylation
protein context
protein–protein interactions
SH3 domains
signaling
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Summary:The assembly of complexes following the detection of extracellular signals is often controlled by signaling proteins comprising multiple peptide binding modules. The SRC homology (SH)3 family represents the archetypical modular protein interaction module, with ~300 annotated SH3 domains in humans that regulate an impressive array of signaling processes. We review recent findings regarding the allosteric contributions of SH3 domains host protein context, their phosphoregulation, and their roles in phase separation that challenge the simple model in which SH3s are considered to be portable domains binding to specific proline-rich peptide motifs. SRC homology (SH)3 domains mediate intramolecular associations and form supramodules with their own supertertiary structures, which regulate their host protein functions.Protein interactions mediated by SH3 modules are highly dependent on the SH3 host protein context in cells.SH3 domain’s functions can be modulated by phosphorylation, which can inhibit protein interactions and/or possibly generate new SH2-dependent associations.Multi-SH3 domain-containing proteins are central to higher-order protein complexes leading to the formation of phase-separated biological condensates.
ISSN:0968-0004
1362-4326
DOI:10.1016/j.tibs.2022.04.005