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 similar to 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.

Automated summary

The assembly of complexes following the detection of extracellular signals is controlled by signaling proteins with multiple peptide binding modules. The SH3 family, with around 300 annotated SH3 domains in humans, is a modular protein interaction module that regulates various signaling processes. Recent findings have challenged the simple model of SH3 domains as portable domains binding to specific proline-rich peptide motifs, by revealing their allosteric contributions in the host protein context, phosphoregulation, and roles in phase separation.