p27 binds cyclin-CDK complexes through a sequential mechanism involving binding-induced protein folding.
p27 controls cell proliferation by binding and regulating nuclear cyclin-dependent kinases (CDKs). In addition, p27 interacts with other nuclear and cytoplasmic targets and has diverse biological functions. We seek to understand how the structural and dynamic properties of p27 mediate its several functions. We show that, despite showing disorder before binding its targets, p27 has nascent secondary structure that may have a function in molecular recognition. Binding to Cdk2-cyclin A is accompanied by p27 folding, and kinetic data suggest a sequential mechanism that is initiated by binding to cyclin A. p27 regulates CDK-cyclin complexes involved directly in cell cycle control and does not interact with other closely related CDKs. We show that p27-cyclin interactions are an important determinant of this specificity and propose that the homologous cell cycle regulators p21 and p57 function by a similar sequential, folding-on-binding mechanism.
Lacy
Eilyn R
ER
Department of Structural Biology, St. Jude Children's Research Hospital, 332, North Lauderdale Street, Memphis, Tennessee 38105, USA.
Filippov
Igor
I
Lewis
William S
WS
Otieno
Steve
S
Xiao
Limin
L
Weiss
Sonja
S
Hengst
Ludger
L
Kriwacki
Richard W
RW
D000595:Amino Acid Sequence; D042846:CDC2-CDC28 Kinases / Q000737:chemistry / Q000378:metabolism*; D017124:Conserved Sequence; D051357:Cyclin-Dependent Kinase 2; D016213:Cyclins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008840:Microfilament Proteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009124:Muscle Proteins; D011487:Protein Conformation; D017510:Protein Folding; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012996:Solutions; D013816:Thermodynamics
D016213:Cyclins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D012996:Solutions; C058992:Tagln protein, mouse; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2