Crystal structures of human pantothenate kinases - Insights into allosteric regulation and mutations linked to a neurodegeneration disordew
Crystal structures of human pantothenate kinases - Insights into allosteric regulation and mutations linked to a neurodegeneration disordew
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DOI：
10.1074/jbc.m701915200
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发表时间：
2007-09-21
影响因子：
4.8
通讯作者：
Park, Hee-Won
中科院分区：
文献类型：
--
作者：
Hong, Bum Soo;Senisterra, Guillermo;Park, Hee-Won
泛酸激酶（PanK）催化CoA生物合成的第一步，并且存在三种表达具有高度保守的催化核心结构域的四种异构体的人类基因。在这里，我们报告了PanK 1 α和PanK 3与乙酰辅酶A（一种反馈抑制剂）复合的催化核心的同源二聚体结构。每个单体采用肌动蛋白激酶超家族的折叠，并且寡核苷酸结合的结构解释了CoA硫酯的变构调节的基础。这些结构也提供了一个机会，以调查的PanK 2突变，已牵连在神经变性的结构效应。对应于PanK 2突变的PanK 3突变蛋白的生物化学和热力学分析显示，具有受损活性和/或稳定性的突变蛋白与疾病早期发作的较高发生率相关。
Pantothenate kinase (PanK) catalyzes the first step in CoA biosynthesis and there are three human genes that express four isoforms with highly conserved catalytic core domains. Here we report the homodimeric structures of the catalytic cores of PanK1 alpha and PanK3 in complex with acetyl-CoA, a feedback inhibitor. Each monomer adopts a fold of the actin kinase superfamily and the inhibitor-bound structures explain the basis for the allosteric regulation by CoA thiciesters. These structures also provide an opportunity to investigate the structural effects of the PanK2 mutations that have been implicated in neurodegeneration. Biochemical and thermodynamic analyses of the PanK3 mutant proteins corresponding to PanK2 mutations show that mutant proteins with compromised activities and/or stabilities correlate with a higher incidence of the early onset of disease.