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Intrinsic disorder mediates the diverse regulatory functions of the Cdk inhibitor p21.


ABSTRACT: Traditionally, well-defined three-dimensional structure has been thought to be essential for protein function. However, myriad biological functions are performed by highly dynamic, intrinsically disordered proteins (IDPs). IDPs often fold upon binding their biological targets and frequently show 'binding diversity' by targeting multiple ligands. We sought to understand the physical basis of IDP binding diversity and report here that the cyclin-dependent kinase (Cdk) inhibitor p21(Cip1) adaptively binds to and inhibits the various Cdk-cyclin complexes that regulate eukaryotic cell division. Using results from NMR spectroscopy and biochemical and cellular assays, we show that structural adaptability of a helical subdomain within p21, termed LH, enables two other subdomains, D1 and D2, to specifically bind conserved surface features of the cyclin and Cdk subunits, respectively, within otherwise structurally distinct Cdk-cyclin complexes. Adaptive folding upon binding is likely to mediate the diverse biological functions of the thousands of IDPs present in eukaryotes.

SUBMITTER: Wang Y 

PROVIDER: S-EPMC3124363 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Intrinsic disorder mediates the diverse regulatory functions of the Cdk inhibitor p21.

Wang Yuefeng Y   Fisher John C JC   Mathew Rose R   Ou Li L   Otieno Steve S   Sublet Jack J   Xiao Limin L   Chen Jianhan J   Roussel Martine F MF   Kriwacki Richard W RW  

Nature chemical biology 20110227 4


Traditionally, well-defined three-dimensional structure has been thought to be essential for protein function. However, myriad biological functions are performed by highly dynamic, intrinsically disordered proteins (IDPs). IDPs often fold upon binding their biological targets and frequently show 'binding diversity' by targeting multiple ligands. We sought to understand the physical basis of IDP binding diversity and report here that the cyclin-dependent kinase (Cdk) inhibitor p21(Cip1) adaptivel  ...[more]

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