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

ABSTRACT: The 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.

SUBMITTER: Spassov DS

PROVIDER: S-EPMC6226010 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Spassov Danislav S DS Ruiz-Saenz Ana A Piple Amit A Moasser Mark M MM

Cell reports 20181001 2

The 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 ...[more]

PMID: 30304684

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Project description:BackgroundThe non-receptor tyrosine kinase Abelson (Abl) is a key player in oncogenesis, with kinase inhibitors serving as paradigms of targeted therapy. Abl also is a critical regulator of normal development, playing conserved roles in regulating cell behavior, brain development and morphogenesis. Drosophila offers a superb model for studying Abl's normal function, because, unlike mammals, there is only a single fly Abl family member. In exploring the mechanism of action of multi-domain scaffolding proteins like Abl, one route is to define the roles of their individual domains. Research into Abl's diverse roles in embryonic morphogenesis revealed many surprises. For instance, kinase activity, while important, is not crucial for all Abl activities, and the C-terminal F-actin binding domain plays a very modest role. This turned our attention to one of Abl's least understood features-the long intrinsically-disordered region (IDR) linking Abl's kinase and F-actin binding domains. The past decade revealed unexpected, important roles for IDRs in diverse cell functions, as sites of posttranslational modifications, mediating multivalent interactions and enabling assembly of biomolecular condensates via phase separation. Previous work deleting conserved regions in Abl's IDR revealed an important role for a PXXP motif, but did not identify any other essential regions.MethodsHere we extend this analysis by deleting the entire IDR, and asking whether Abl∆IDR rescues the diverse roles of Abl in viability and embryonic morphogenesis in Drosophila.ResultsThis revealed that the IDR is essential for embryonic and adult viability, and for cell shape changes and cytoskeletal regulation during embryonic morphogenesis, and, most surprisingly, revealed a role in modulating protein stability.ConclusionOur data provide new insights into the role of the IDR in an important signaling protein, the non-receptor kinase Abl, suggesting that it is essential for all aspects of protein function during embryogenesis, and revealing a role in protein stability. These data will stimulate new explorations of the mechanisms by which the IDR regulates Abl stability and function, both in Drosophila and also in mammals. They also will stimulate further interest in the broader roles IDRs play in diverse signaling proteins. Video Abstract.

Dataset Information

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

Publications

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

Similar Datasets

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