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Structural basis for regulation of human acetyl-CoA carboxylase
Nature ( IF 64.8 ) Pub Date : 2018-06-01 , DOI: 10.1038/s41586-018-0201-4
Moritz Hunkeler , Anna Hagmann , Edward Stuttfeld , Mohamed Chami , Yakir Guri , Henning Stahlberg , Timm Maier

Acetyl-CoA carboxylase catalyses the ATP-dependent carboxylation of acetyl-CoA, a rate-limiting step in fatty acid biosynthesis1,2. Eukaryotic acetyl-CoA carboxylases are large, homodimeric multienzymes. Human acetyl-CoA carboxylase occurs in two isoforms: the metabolic, cytosolic ACC1, and ACC2, which is anchored to the outer mitochondrial membrane and controls fatty acid β-oxidation1,3. ACC1 is regulated by a complex interplay of phosphorylation, binding of allosteric regulators and protein–protein interactions, which is further linked to filament formation1,4–8. These filaments were discovered in vitro and in vivo 50 years ago7,9,10, but the structural basis of ACC1 polymerization and regulation remains unknown. Here, we identify distinct activated and inhibited ACC1 filament forms. We obtained cryo-electron microscopy structures of an activated filament that is allosterically induced by citrate (ACC–citrate), and an inactivated filament form that results from binding of the BRCT domains of the breast cancer type 1 susceptibility protein (BRCA1). While non-polymeric ACC1 is highly dynamic, filament formation locks ACC1 into different catalytically competent or incompetent conformational states. This unique mechanism of enzyme regulation via large-scale conformational changes observed in ACC1 has potential uses in engineering of switchable biosynthetic systems. Dissecting the regulation of acetyl-CoA carboxylase opens new paths towards counteracting upregulation of fatty acid biosynthesis in disease.Cryo-electron microscopy studies of distinct, catalytically active and inactive filaments of human acetyl-CoA carboxylase 1 reveal the structural basis of its regulation.

中文翻译:

调节人乙酰辅酶A羧化酶的结构基础

乙酰辅酶A羧化酶催化乙酰辅酶A的ATP依赖性羧化,这是脂肪酸生物合成中的限速步骤1,2。真核乙酰辅酶 A 羧化酶是大的同二聚体多酶。人乙酰辅酶A羧化酶以两种同工型存在:代谢性、胞质ACC1和ACC2,后者锚定在线粒体外膜上并控制脂肪酸β-氧化1,3。ACC1 受磷酸化、变构调节剂的结合和蛋白质-蛋白质相互作用的复杂相互作用的调节,这进一步与细丝形成有关 1,4-8。这些细丝是 50 年前在体外和体内发现的7,9,10,但 ACC1 聚合和调节的结构基础仍然未知。在这里,我们确定了不同的激活和抑制的 ACC1 细丝形式。我们获得了由柠檬酸盐(ACC-柠檬酸盐)变构诱导的活化细丝的冷冻电子显微镜结构,以及由乳腺癌 1 型易感蛋白(BRCA1)的 BRCT 结构域结合产生的灭活细丝形式。虽然非聚合 ACC1 是高度动态的,但细丝形成将 ACC1 锁定为不同的催化能力或无能力的构象状态。这种通过在 ACC1 中观察到的大规模构象变化来调节酶的独特机制在可切换生物合成系统的工程中具有潜在的用途。剖析乙酰辅酶 A 羧化酶的调控开辟了对抗疾病中脂肪酸生物合成上调的新途径。
更新日期:2018-06-01
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