一个在衰老过程中调节蛋白质-蛋白质相互作用的保守烟酰胺腺嘌呤二核苷酸（NAD）结合口袋。
A conserved NAD binding pocket that regulates protein-protein interactions during aging.
作者信息
Li Jun, Bonkowski Michael S, Moniot Sébastien, Zhang Dapeng, Hubbard Basil P, Ling Alvin J Y, Rajman Luis A, Qin Bo, Lou Zhenkun, Gorbunova Vera, Aravind L, Steegborn Clemens, Sinclair David A
机构信息
Department of Genetics, Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA.
Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany.
出版信息
Science. 2017 Mar 24;355(6331):1312-1317. doi: 10.1126/science.aad8242.
Abstract
DNA repair is essential for life, yet its efficiency declines with age for reasons that are unclear. Numerous proteins possess Nudix homology domains (NHDs) that have no known function. We show that NHDs are NAD (oxidized form of nicotinamide adenine dinucleotide) binding domains that regulate protein-protein interactions. The binding of NAD to the NHD domain of DBC1 (deleted in breast cancer 1) prevents it from inhibiting PARP1 [poly(adenosine diphosphate-ribose) polymerase], a critical DNA repair protein. As mice age and NAD concentrations decline, DBC1 is increasingly bound to PARP1, causing DNA damage to accumulate, a process rapidly reversed by restoring the abundance of NAD Thus, NAD directly regulates protein-protein interactions, the modulation of which may protect against cancer, radiation, and aging.
摘要
DNA修复对生命至关重要，但其效率会随年龄增长而下降，原因尚不清楚。许多蛋白质拥有功能未知的Nudix同源结构域（NHDs）。我们发现NHDs是调节蛋白质-蛋白质相互作用的烟酰胺腺嘌呤二核苷酸（NAD，烟酰胺腺嘌呤二核苷酸的氧化形式）结合结构域。NAD与乳腺癌缺失1（DBC1）的NHD结构域结合会阻止它抑制PARP1[聚（腺苷二磷酸核糖）聚合酶]，这是一种关键的DNA修复蛋白。随着小鼠衰老且NAD浓度下降，DBC1越来越多地与PARP1结合，导致DNA损伤积累，而恢复NAD丰度可迅速逆转这一过程。因此，NAD直接调节蛋白质-蛋白质相互作用，对其进行调节可能预防癌症、辐射和衰老。
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