Structural and functional elucidation of the peroxisomal AAA+ complex

过氧体是一种被膜包裹的细胞器，负责氧化代谢过程，如过氧化物质或脂肪酸的分解和乙醚磷脂的形成。在酵母中，至少有32种所谓的Pex蛋白负责过氧化物体的生物发生和维持。Pex1和Pex6是AAA+(与多种细胞活动相关的ATPase)超家族的ATPase，它驱动折叠蛋白穿过过氧化体膜的运输。这两种蛋白质对过氧化物体的生物发生都是必不可少的。人类Pex1和Pex6的突变是导致Zellweger综合征谱系的严重常染色体隐性遗传病的最常见原因。该项目的目的是利用冷冻电子显微镜和单粒子分析来表征人Pex1/6复合体的结构和功能。为此，将从结构上表示复合体工作周期中构象变化的快照，并将研究Pex1和Pex6之间的相互作用。此外，将从生化和结构上检验Pex1显著突变的影响。

Peroxisomes are membrane-encapsulated cell organelles which are responsible for life-threatening oxidative metabolic processes such as the breakdown of peroxides or fatty acids and the formation of ether phospholipids. In yeast, at least 32 so-called Pex proteins are responsible for the biogenesis and maintenance of peroxisomes. Pex1 and Pex6 are ATPases of the AAA + (ATPases associated with various cellular activities) superfamily that drive the transport of folded proteins across the peroxisomal membrane. Both proteins are essential for peroxisomal biogenesis. Mutations in human Pex1 and Pex6 are the most common cause of severe autosomal recessive diseases of the Zellweger syndrome spectrum. The aim of the project is the structural and functional characterization of the human Pex1 / 6 complex using cryo-electron microscopy and single particle analysis. For this purpose, snapshots of the conformational changes during a working cycle of the complex will be structurally represented and the interaction between Pex1 and Pex6 will be investigated. Furthermore, the effects of a prominent mutation in Pex1 will be examined biochemically and structurally.