Molecular mechanisms underlying myotubularin-related phosphoinositide 3-phosphatase function in health and disease

肌管蛋白相关磷酸肌醇 3-磷酸酶在健康和疾病中功能的分子机制

• 批准号: 527884344
• 负责人: Professor Volker Haucke, Ph.D.
• 金额: --
• 依托单位: Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/527884344?language=en
• 关键词: Molecular; mechanisms; underlying; myotubularin; related

Phosphoinositides (PIs) are a minor class of short-lived membrane phospholipids that mediate crucial cellular and organismal functions. PI 3-phosphates can be produced at the cell surface during signalling, but are mainly found in the endolysosomal system. Turnover of PI 3-phosphates is accomplished by several types of PI phosphatases, most notably the myotubularin family (i.e. MTMs), which has been closely linked to human disease. The MTM family comprises 15 members that differ with respect to domain structure, presumed localization, and catalytic activity. Major questions related to MTM localization, function, and regulation remain unanswered. Based on our previous studies and preliminary results we hypothesize that the recruitment and activation of MTMRs and their complexes to endosomes or lysosomes is mediated by their association with proteins (e.g. Rabs) and is controlled by nutrient signals (e.g. via protein kinases or phosphatases). The overarching objectives of the proposed research therefore are to (i) define the nanoscale localization and function of the catalytically active MTMRs MTM1, R1, R2, R7, and R14, and of MTMR12 (i.e. the inactive binding partner of MTM1) (ii) to molecularly define the mechanisms by which these MTMRs undergo complex formation and associate with their recruitment factors (e.g. proteins), and, finally, (iii) to dissect the regulatory network that controls MTMR function in response to physiological or pathophysiological stimuli (e.g. starvation, lysosomal damage). We expect these studies to provide new insights into the physiological regulation of MTMR-based signaling and its interplay with nutrient signaling and, eventually cell metabolism and/ or cell stress. Such information is critical for the development of novel therapies to treat human diseases linked to MTMR dysfunction.

磷脂酰肌醇(PI)是一类短命的膜磷脂，调节重要的细胞和组织功能。PI-3-磷酸在信号传递过程中可在细胞表面产生，但主要存在于内溶酶体系统中。PI 3-磷酸的周转是由几种类型的PI磷酸酶完成的，最著名的是肌管蛋白家族(即MTM)，它与人类疾病密切相关。MTM家族由15个成员组成，这些成员在结构域结构、推测的定位和催化活性方面存在差异。与MTM的本地化、功能和监管相关的主要问题仍未得到解答。根据我们以前的研究和初步结果，我们假设MTMR及其复合体向内体或溶酶体的募集和激活是由它们与蛋白质(例如RABS)的结合所介导的，并受到营养信号的控制(例如通过蛋白激酶或磷酸酶)。因此，这项研究的主要目标是(I)确定具有催化活性的MTMR MTM1、R1、R2、R7和R14以及MTMR12(即MTM1的非活性结合伙伴)的纳米尺度定位和功能；(Ii)从分子上确定这些MTMR经历复杂的形成并与它们的招募因子(例如蛋白质)相关联的机制；以及(Iii)剖析控制MTMR功能的调控网络，以响应生理或病理生理刺激(例如饥饿、溶酶体损伤)。我们期待这些研究为基于MTMR的信号的生理调控以及它与营养信号的相互作用，最终与细胞代谢和/或细胞应激提供新的见解。这些信息对于开发治疗与MTMR功能障碍有关的人类疾病的新疗法至关重要。