1d9s
TUMOR SUPPRESSOR P15(INK4B) STRUCTURE BY COMPARATIVE MODELING AND NMR DATA
Structural highlights
FunctionCDN2B_MOUSE Interacts strongly with CDK4 and CDK6. Potent inhibitor. Potential effector of TGF-beta induced cell cycle arrest (By similarity). Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe INK4 (inhibitor of cyclin-dependent kinase 4) family consists of four tumor-suppressor proteins: p15(INK4B), p16(INK4A), p18(INK4C), and p19(INK4D). While their sequences and structures are highly homologous, they show appreciable differences in conformational flexibility, stability, and aggregation tendency. Here, p16 and p18 were first compared directly by NMR for line broadening and disappearance, then investigated by three different approaches in search of the causes of these differences. From denaturation experiments it was found that both proteins are marginally stable with low denaturation stability (1.94 and 2.98 kcal/mol, respectively). Heteronuclear (1)H-(15)N nuclear Overhauser enhancement measurements revealed very limited conformational flexibility on the pico- to nanosecond time-scale for both p16 and p18. H/(2)H exchange of amide protons monitored by NMR on three proteins (p16, p18 as well as p15), however, revealed markedly different rates in the order p18<p16</=p15. A subset of very slowly exchanging residues (about 19 in total) was identified in p18, including 16 residues in the region of the fourth ankyrin repeat, probably as a result of a stabilizing effect by the extra ankyrin repeat. Thus, while INK4 proteins may have similar low thermodynamic stability as well as limited flexibility on the pico- to nanosecond time-scale, they display pronounced differences in the conformational flexibility on the time-scale of minutes to hours. Further analyses suggested that differences in H/(2)H exchange rates reflect differences in the kinetic stability of the INK4 proteins, which in turn is related to differences in the aggregation tendency. Tumor suppressor INK4: comparisons of conformational properties between p16(INK4A) and p18(INK4C).,Yuan C, Li J, Selby TL, Byeon IJ, Tsai MD J Mol Biol. 1999 Nov 19;294(1):201-11. PMID:10556039[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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