Role of prohibitins for proteolytic processes within mitochondria

Prohibitins包括一个保守的、普遍存在的真核蛋白家族，它们与真核细菌的HflK和Hflc序列相似，它们是AAA蛋白酶FtsH的调节蛋白。Prohibitins定位于线粒体内膜，在那里它们形成一个高分子质量的复合体，并与m-AAA蛋白酶组装。我们观察到酵母线粒体中缺乏抑制素的m-AAA蛋白酶加速了内膜蛋白的降解，这表明AAA蛋白酶的调节从真细菌到真核生物都是保守的。在拟议的研究项目中，我们将描述抑制素在膜蛋白降解过程中的调节作用。尤其有兴趣的是检查禁止素复合体是否在蛋白分解过程中发挥伴侣活性和/或影响m-AAA蛋白酶的酶活性。我们将进一步表征禁忌素复合体的生物发生，并通过电子显微镜分析纯化的复合体的结构组织。遗传、合成、致死和抑制筛选的目的是识别线粒体中禁忌素的功能相互作用伙伴。这些研究还应该揭示线粒体内膜蛋白的周转与多种细胞功能之间的潜在联系，包括衰老、细胞周期调节和癌症，以及线粒体形态的维持。

Prohibitins comprise a conserved and ubiquitous family of eukaryotic proteins which exhibit sequence similarity to eubacterial HflK and HflC, regulatory proteins of the AAA protease FtsH. Prohibitins are localised to the mitochondrial inner membrane where they form a high molecular mass complex and assemble with the m-AAA protease. We observed an accelerated degradation of inner membrane proteins by the m-AAA protease in yeast mitochondria lacking prohibitins pointing to a regulation of AAA proteases which is conserved from eubacteria to eukaryotes. In the proposed research project, we will characterise the regulatory role of prohibitins during membrane protein degradation. It will be of particular interest to examine whether the prohibitin complex exerts chaperone activity during proteolysis and/or affects the enzymatic activity of the m-AAA protease. We will furthermore characterise the biogenesis of the prohibitin complex and analyse the structural organisation of purified complexes by electron microscopy. Genetic synthetic lethal and suppressor screens aim at the identification of functional interaction partners of prohibitins in mitochondria. These studies should also reveal a potential link between the turnover of mitochondrial inner membrane proteins and diverse cellular functions previously attributed to prohibitins including senescence, cell cycle regulation and cancer, and the maintenance of mitochondrial morphology