title: 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.
authors.affiliation: Departments of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Yuefeng
authors.initials: Y
authors.lastname: Wang
authors.forename: John C
authors.initials: JC
authors.lastname: Fisher
authors.forename: Rose
authors.initials: R
authors.lastname: Mathew
authors.forename: Li
authors.initials: L
authors.lastname: Ou
authors.forename: Steve
authors.initials: S
authors.lastname: Otieno
authors.forename: Jack
authors.initials: J
authors.lastname: Sublet
authors.forename: Limin
authors.initials: L
authors.lastname: Xiao
authors.forename: Jianhan
authors.initials: J
authors.lastname: Chen
authors.forename: Martine F
authors.initials: MF
authors.lastname: Roussel
authors.forename: Richard W
authors.initials: RW
authors.lastname: Kriwacki
mesh_terms: D000595:Amino Acid Sequence; D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D056890:Eukaryota / Q000166:cytology / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018844:Cyclin-Dependent Kinases