Renner C, Baumgartner R, Noegel A A, Holak T A
Max Planck Institute for Biochemistry, Martinsried, D-82152, Germany.
J Mol Biol. 1998;283(1):221-9. doi: 10.1006/jmbi.1998.2079.
The four members of the INK4 gene family, p16(INK4a), p15(INK4b), p18(INK4c) and p19(INK4d), are known to bind to and inhibit the closely related cyclin-dependent kinases CDK4 and CDK6 as part of the regulation of the G1/S transition in the cell division cycle. Loss of INK4 gene product function, and particularly that of p16(INK4a), is found in human cancer. 15N NMR relaxation rates of p19(INK4d) were analyzed using the reduced spectral density mapping method. Most of the backbone of p19(INK4d) exists in a well-defined structure of limited conformational flexibility on the nanosecond to picosecond time-scales. Introducing appropriate scaling to account for the effects of anisotropy, a considerable amount of exchange broadening was found for several residues throughout the sequence, especially residues in the second ankyrin repeat and in the beginnings and ends of loops connecting ankyrin repeats. A possible mode of binding between p19(INK4d) and CDK4 and CDK6 could therefore involve the loop segments of p19(INK4d). The average overall correlation time taumeff was determined to be 13.6 ns, reflecting the tendency of p19(INK4d) to aggregate.
INK4基因家族的四个成员，即p16(INK4a)、p15(INK4b)、p18(INK4c)和p19(INK4d)，已知可结合并抑制密切相关的细胞周期蛋白依赖性激酶CDK4和CDK6，作为细胞分裂周期中G1/S转换调节的一部分。INK4基因产物功能的丧失，尤其是p16(INK4a)的功能丧失，在人类癌症中被发现。使用简化谱密度映射方法分析了p19(INK4d)的15N NMR弛豫率。在纳秒到皮秒的时间尺度上，p19(INK4d)的大部分主链存在于构象灵活性有限的明确结构中。引入适当的标度以考虑各向异性的影响，发现在整个序列中有几个残基存在相当数量的交换展宽，特别是在第二个锚蛋白重复序列以及连接锚蛋白重复序列的环的起始和末端的残基。因此，p19(INK4d)与CDK4和CDK6之间可能的结合模式可能涉及p19(INK4d)的环段。平均总相关时间taumeff被确定为13.6 ns，反映了p19(INK4d)聚集的趋势。
