编者按：众所周知，乳腺癌易感基因（BRCA）属于抑癌基因，其编码的BRCA蛋白属于抑癌因子。BRCA突变后，失去抑癌作用，于是容易发生乳腺癌。既往研究发现，BRCA蛋白羧基末端（BRCT）结构域与乙酰辅酶A羧化酶（ACC）结合后，可使ACC失活。ACC为脂肪酸生物合成第一阶段限速酶，对于脂肪代谢具有关键作用，其激活与肥胖相关疾病和肿瘤生长相关。ACC为大分子同型二联聚合酶，由生物素羧基载体蛋白、生物素羧化酶以及羧基转移酶酶构成，可以将乙酰辅酶A、碳酸氢根和三磷酸腺苷（ATP）催化为丙二酰辅酶A、二磷酸腺苷和磷。人类ACC以两种异构体形式出现：ACC1和ACC2，其锁定于线粒体外膜，并且控制脂肪酸β氧化。ACC1受到磷酸化复杂相互作用、变构调节剂结合、蛋白质与蛋白质相互作用的调控，进一步与酶丝形成相关。50年前，体外和体内研究已经发现这些酶丝，但是ACC1聚合和调控的结构基础尚不明确。
2018年6月13日，全球自然科学三大旗舰期刊之一、英国《自然》正刊在线发表瑞士巴塞尔大学、美国哈佛大学医学院达纳法伯癌症研究所的研究报告，明确了ACC1酶丝不同的激活和抑制形式。
该研究获得了ACC1酶丝两种不同形式的低温电子显微镜结构：通过柠檬酸盐变构诱导产生的激活酶丝、通过与BRCT结构域结合产生的失活酶丝。虽然未聚合ACC1高度活跃，但是激活或失活酶丝的形成，将ACC1锁定于不同的催化活性或无活性构象状态。
因此，该研究通过观察ACC1的构象变化，发现了调控该酶的独特机制，对于可转换生物合成系统工程具有潜在用途。ACC是代谢酶调节丝形成的教科书式范例，该研究通过深入解析ACC调控，为抑制疾病脂肪酸生物合成过度开辟了新的途径。该研究通过明确ACC酶丝的不同相互作用，为体外和体内调控ACC聚合奠定了基础，例如针对ACC过度激活的靶向治疗干预。
相关阅读
Nature. 2018 Jun 13. [Epub ahead of print]
Structural basis for regulation of human acetyl-CoA carboxylase.
Moritz Hunkeler, Anna Hagmann, Edward Stuttfeld, Mohamed Chami, Yakir Guri, Henning Stahlberg, Timm Maier.
University of Basel, Basel, Switzerland; Dana-Farber Cancer Institute, Boston, MA, USA.
Acetyl-CoA carboxylase catalyses the ATP-dependent carboxylation of acetyl-CoA, a rate-limiting step in fatty acid biosynthesis. 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-oxidation. ACC1 is regulated by a complex interplay of phosphorylation, binding of allosteric regulators and protein-protein interactions, which is further linked to filament formation. These filaments were discovered in vitro and in vivo 50 years ago, 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.
DOI: 10.1038/s41586-018-0201-4
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