The structural plasticity of the C terminus of p21Cip1 is a determinant for target protein recognition.
The cyclin-dependent kinase inhibitory protein p21(Cip1) might play multiple roles in cell-cycle regulation through interaction of its C-terminal domain with a defined set of cellular proteins such as proliferating cell nuclear antigen (PCNA), calmodulin (CaM), and the oncoprotein SET. p21(Cip1) could be described as an intrinsically unstructured protein in solution although the C-terminal domain adopts a well-defined extended conformation when bound to PCNA. However, the molecular mechanism of the interaction with CaM and the oncoprotein SET is not well understood, partly because of the lack of structural information. In this work, a peptide derived from the C-terminal domain of p21(Cip1) that covers the binding domain of the three above-mentioned proteins was used to demonstrate that the C-terminal domain of p21 recognizes multiple ligands through its ability to adopt multiple conformations. The conformation is dictated by tertiary contacts rather than by the primary sequence of the protein. Our results suggest that the C-terminal domain of p21(Cip1) adopts an extended structure when bound to PCNA and probably when bound to the oncoprotein SET, but an alpha helix when bound to CaM.
Esteve
Vicent
V
Dept. Bioquímica i Biologia Molecular, Universitat de València, 46100 Burjassot, València, Spain.
Canela
Núria
N
Rodriguez-Vilarrupla
Aina
A
Aligué
Rosa
R
Agell
Neus
N
Mingarro
Ismael
I
Bachs
Oriol
O
Pérez-Payá
Enrique
E
D001667:Binding, Competitive; D002147:Calmodulin / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D002868:Chromosomal Proteins, Non-Histone; D002942:Circular Dichroism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000737:chemistry* / Q000378:metabolism; D004268:DNA-Binding Proteins; D004926:Escherichia coli / Q000235:genetics; D056488:Histone Chaperones; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D011487:Protein Conformation; D011506:Proteins / Q000378:metabolism*; D014157:Transcription Factors
C493956:CDKN1A protein, human; D002147:Calmodulin; D002868:Chromosomal Proteins, Non-Histone; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D008024:Ligands; D010446:Peptide Fragments; D018809:Proliferating Cell Nuclear Antigen; D011506:Proteins; C513473:SET protein, human; D014157:Transcription Factors