SH3 domain

The SH3 domain (Src Homology 3 domain) is a small protein domain of about 60 amino acids that is found in a variety of proteins involved in intracellular signaling pathways. It is named after its discovery in the Src oncoprotein, a non-receptor tyrosine kinase. SH3 domains are known for their role in mediating protein-protein interactions by binding to proline-rich motifs in target proteins.

Structure

The SH3 domain is characterized by a beta-barrel fold composed of five or six beta-strands arranged as two tightly packed anti-parallel beta-sheets. This structure forms a compact, globular domain that is highly conserved across different species. The domain typically recognizes and binds to proline-rich sequences, often containing the consensus motif PxxP, where "P" represents proline and "x" is any amino acid.

Function

SH3 domains are involved in the regulation of various cellular processes, including:

• Signal transduction: SH3 domains facilitate the assembly of signaling complexes by mediating interactions between proteins involved in pathways such as the MAPK/ERK pathway.
• Cytoskeletal organization: They play a role in the regulation of the actin cytoskeleton by interacting with proteins such as dynamin and cortactin.
• Endocytosis: SH3 domains are involved in the internalization of cell surface receptors and other molecules through clathrin-mediated endocytosis.

Binding Specificity

The specificity of SH3 domain interactions is determined by the sequence and conformation of the proline-rich motifs they bind. Variations in the amino acids surrounding the PxxP motif can influence binding affinity and specificity. Some SH3 domains have been shown to bind to non-canonical sequences, expanding their functional repertoire.

Clinical Significance

Mutations or dysregulation of SH3 domain-containing proteins can lead to various diseases, including cancer, immunodeficiencies, and neurological disorders. For example, mutations in the SH3 domain of the Src family kinases can result in aberrant signaling and contribute to oncogenesis.

Research Techniques

Several techniques are used to study SH3 domains and their interactions, including:

• X-ray crystallography and NMR spectroscopy for structural analysis.
• Yeast two-hybrid screening and co-immunoprecipitation for identifying protein-protein interactions.
• Site-directed mutagenesis to investigate the functional roles of specific residues within the SH3 domain.

Also see

• Src family kinases
• Protein-protein interaction
• Signal transduction
• Proline-rich motif