A Dimerization Function in the Intrinsically Disordered N-Terminal Region of Src

Abstract

SUMMARYThe mode of regulation of Src kinases has been elucidated by crystallographic studies identifying conserved structured protein modules involved in an orderly set of intramolecular associations and ligand interactions. Despite these detailed insights, much of the complex behavior and diversity in the Src family remains unexplained. A key missing piece is the function of the unstructured N-terminal region. We report here the function of the N-terminal region in binding within a hydrophobic pocket in the kinase domain of a dimerization partner. Dimerization substantially enhances autophosphorylation and phosphorylation of selected substrates, and interfering with dimerization is disruptive to these functions. Dimerization and Y419 phosphorylation are codependent events creating a bistable switch. Given the versatility inherent in this intrinsically disordered region, its multisite phosphorylations, and its divergence within the family, the unique domain likely functions as a central signaling hub overseeing much of the activities and unique functions of Src family kinases.

Considerations of Antibody Geometric Constraints on NK Cell Antibody Dependent Cellular Cytotoxicity

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“…In addition to improve the spatial resolutionof CRY2-system 12 , engineering OS revealed new functions of SRC conformational intermediates or domains. Despite being mostly described as a monomer, SRC can dimerize and oligomerize after opening of its conformation 8,10 . In addition to the SH2 domain mediated regulation for SRC focal adhesion targeting, our synthetic OS revealed that SRC oligomerization is a stabilizing process in adhesive sites mediated by SH3 domains.…”

“…Second, interactions with lipids add an additional layer of complexity by affecting the binding capacities of the poorly structured UD and SH3 domains 7 . Third, this complexity also includes the level of clustering of this kinase while being able to oligomerized from the poorly knowns c-SRC dimers to 80 nm-nanoclusters of c-SRC molecules [8][9][10] . The vast amount of SRC conformational intermediates suggests that c-SRC signaling emerges from a heterogeneous population of molecules with different levels of kinase activity targeting dynamically a repertoire of interactors.…”

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