Human sirt-1: molecular modeling and structure-function relationships of an unordered protein.
Human sirt-1: molecular modeling and structure-function relationships of an unordered protein.
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DOI：
10.1371/journal.pone.0007350
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发表时间：
2008-10-08
期刊：
影响因子：
3.7
通讯作者：
Colonna G
中科院分区：
文献类型：
--
作者：
Autiero I;Costantini S;Colonna G
Sirt-1是一种由747个氨基酸残基组成的NAD+依赖性核脱乙酰酶，在哺乳动物中参与多种重要的代谢途径，如葡萄糖代谢和胰岛素分泌，并且通常作为多功能蛋白作用于许多不同的代谢底物。Sirt-1下调p53活性，延长寿命和细胞存活;它还使过氧化物酶体增殖物激活受体-γ（PPAR-γ）及其辅激活因子1 α（PGC-1α）脱乙酰化，促进脂质动员，积极调节胰岛素分泌，增加线粒体尺寸和数量。因此，它与糖尿病和代谢综合征等疾病有关，也与热量限制引起的长寿机制有关。它的整个结构还没有实验确定，其变构位点的结构特征是未知的，也没有关于其变构效应物结合所决定的结构变化的信息。在这项研究中，我们模拟了整个三维结构的Sirt-1和它的内源性激活剂，核蛋白AROS。此外，我们模拟了Sirt-1/AROS复合物，以研究其激活和调节的结构基础。令人惊讶的是，结构数据表明，Sirt-1是一个无序的蛋白质，具有一个球状的核心和两个大的无序结构区域在两端，这在蛋白质-蛋白质相互作用中起着重要的作用。此外，我们还发现在Sirt-1上存在一个保守的药效团口袋，并对其意义进行了讨论。
Sirt-1 is a NAD+-dependent nuclear deacetylase of 747 residues that in mammals is involved in various important metabolic pathways, such as glucose metabolism and insulin secretion, and often works on many different metabolic substrates as a multifunctional protein. Sirt-1 down-regulates p53 activity, rising lifespan, and cell survival; it also deacetylases peroxisome proliferator-activated receptor-gamma (PPAR-γ) and its coactivator 1 alpha (PGC-1α), promoting lipid mobilization, positively regulating insulin secretion, and increasing mitochondrial dimension and number. Therefore, it has been implicated in diseases such as diabetes and the metabolic syndrome and, also, in the mechanisms of longevity induced by calorie restriction. Its whole structure is not yet experimentally determined and the structural features of its allosteric site are unknown, and no information is known about the structural changes determined by the binding of its allosteric effectors. In this study, we modelled the whole three-dimensional structure of Sirt-1 and that of its endogenous activator, the nuclear protein AROS. Moreover, we modelled the Sirt-1/AROS complex in order to study the structural basis of its activation and regulation. Amazingly, the structural data show that Sirt-1 is an unordered protein with a globular core and two large unordered structural regions at both termini, which play an important role in the protein-protein interaction. Moreover, we have found on Sirt-1 a conserved pharmacophore pocket of which we have discussed the implication.
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