Crystal Structure of the Src Family Kinase Hck SH3-SH2 Linker Regulatory Region Supports an SH3-dominant Activation Mechanism.

摘要: Most mammalian cell types depend on multiple Src family kinases (SFKs) to regulate diverse signaling pathways. Strict control of SFK activity is essential for normal cellular function, and loss kinase regulation contributes several forms cancer other diseases. Previous x-ray crystal structures the SFKs c-Src Hck revealed that intramolecular association their homology (SH) 3 domains SH2 linker regions has a key role in down-regulation activity. However, amino acid sequence represents suboptimal ligand isolated SH3 domain, suggesting it may form polyproline type II helical conformation required docking only context intact structure. To test this hypothesis directly, we determined structure truncated protein consisting plus linker. Despite absence relative orientations shorter were very similar those observed near full-length, down-regulated Hck. adopted modified topology failed engage domain. This new supports idea these noncatalytic work together as "conformational switch" modulates manner unique domain topologies present protein. Our results also provide fresh structural insight into facile induction by HIV-1 Nef binding proteins implicate existence innate conformational states individual members "fine-tune" sensitivities activation SH3-based ligands.