期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 353, 期 5, 页码 1118-1128出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2005.08.074
关键词
p27; cyclin-dependant kinase; intrinsically unstructured; NMR; molecular dynamics
资金
- NCI NIH HHS [CA21765, CA82491] Funding Source: Medline
- NIGMS NIH HHS [GM57513] Funding Source: Medline
p2(Kip1) (p27) influences cell division by regulating nuclear cyclindependent kinases. Before binding, p27 is at least partially disordered and folds upon binding its Cdk/cyclin targets. 30-40% of human proteins, including p27, are predicted to contain disordered segments, and have been termed intrinsically unstructured proteins (IUPs). Unfortunately, the inherent dynamics of IUPs hamper detailed analysis of their structure/ function relationships. Here, we describe the use of molecular dynamics (MD) computations and solution NMR spectroscopy to reveal that several segments of the p27 kinase inhibitory domain (p27-KID), in addition to the previously characterized helical segment, exist as highly populated, intrinsically folded structural units (IFSUs). Several IFSUs resemble structural features of bound p27-KID, while another exhibits alternative conformations. Interestingly, the highly conserved, specificity determining segment of p27 is shown to be highly disordered. Elucidation of IFSUs within p27-KID allows consideration of their influences on the thermodynamics and kinetics of Cdk/cyclin binding. The degree to which IFSUs are populated within p27-KID is surprising and suggests that other putative IUPs contain IFSUs that may be studied using similar techniques. (c) 2005 Elsevier Ltd. All rights reserved.
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