Structural basis of SIRT2 pre-catalysis NAD+ binding dynamics and mechanism.

IF 3.1 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Nan Zhang, Kah Chee Pow, Lanfang Chen, Quan Hao
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引用次数: 0

Abstract

Sirtuins are an evolutionarily conserved family of NAD+-dependent deacylases whose catalytic mechanism remains under active investigation. While previous studies have captured sirtuin reaction intermediates using thioacetyl-lysine analogs, here we report six crystal structures of human SIRT2 in complex with native myristoylated peptides and NAD+, revealing the sequence of changes from initial NAD+ binding to the formation of intermediate I. Our structures provide direct structural evidence for: (1) zinc-binding domain shift during NAD+ entry, (2) water-mediated hydrogen-bond formation that disrupts nicotinamide aromaticity preceding cleavage, and (3) the formation of intermediate I. Additionally, we determined the structures of two functionally critical mutants (SIRT2F96A and SIRT2H187A), demonstrating their roles in stabilizing NAD+ in a productive conformation. These findings complete the comprehensive structural framework for the sirtuin deacylation mechanism and highlight key residues governing catalytic efficiency.

SIRT2预催化NAD+结合动力学及机制的结构基础。
Sirtuins是一个进化上保守的NAD+依赖脱羧酶家族,其催化机制仍在积极研究中。虽然之前的研究使用硫代乙酰赖氨酸类似物捕获了sirtuin反应中间体,但在这里,我们报道了人类SIRT2与天然豆豆酰化肽和NAD+复合物的六种晶体结构,揭示了从最初的NAD+结合到中间体i形成的变化顺序。我们的结构为以下方面提供了直接的结构证据:(1) NAD+进入过程中锌结合结构域的移位;(2)水介导的氢键形成,在裂解前破坏烟酰胺的芳香性;(3)中间体i的形成。此外,我们确定了两个功能关键突变体(SIRT2F96A和SIRT2H187A)的结构,证明了它们在稳定NAD+生产构象中的作用。这些发现完成了sirtuin去酰化机制的全面结构框架,并突出了控制催化效率的关键残基。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
6.10
自引率
0.00%
发文量
128
审稿时长
10 weeks
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