Membrane protein biogenesis at the ER

项目摘要/摘要 我的小组试图从分子细节上理解每一类主要膜所采取的步骤 蛋白质达到其fiNAL组装状态。大约四分之一的基因编码膜蛋白。 fi被插入原核生物的质膜或内质网(ER) 真核生物。这些蛋白质执行许多基本功能，如受体、通道、酶、锚和 传送者。膜蛋白的生物合成是一个固有的ffi过程，许多人类 疾病与膜蛋白折叠缺陷有关。因此，了解膜蛋白是如何 是细胞生物学中的一个基本问题，对人类的治疗具有重要的意义 疾病。 在人类基因组编码的约5,000种膜蛋白中，大多数都有不止一种 跨膜结构域。然而，我们对这些“多通道”蛋白质如何插入、折叠和 组装成功能实体还处于早期阶段。在过去的几年里，我所在的团队的工作使我们 在内质网中发现一个新的~390 kDa易位基因，参与大多数多通道的生物发生 人类细胞中的膜蛋白。我们现在主要关注的是Defi的分子机制 这一过程使用了一套生化、结构、细胞生物学、遗传学和生物信息学的跨学科 接近了。这些研究有望为膜的基本生物学挑战提供新的见解。 蛋白质生物发生。

PROJECT SUMMARY/ABSTRACT My group seeks to understand, in molecular detail, the steps taken by each of the major classes of membrane proteins to achieve their final assembled state. About one-quarter of all genes code for membrane proteins that are first inserted into the plasma membrane of prokaryotes or the endoplasmic reticulum (ER) of eukaryotes. These proteins perform many essential functions as receptors, channels, enzymes, anchors and transporters. Biosynthesis of membrane proteins is an inherently inefficient process, and numerous human diseases are linked to defective folding of membrane proteins. Thus, understanding how membrane proteins are made is a fundamental question in cell biology with important implications for the treatment of human diseases. Of the ~5,000 membrane proteins coded in the human genome, the majority have more than one transmembrane domain. Yet our understanding of how these “multi-pass” proteins are inserted, folded and assembled into functional entities is at an early stage. Work in my group over the past several years led us to discover a novel ~390 kDa translocon in the ER that is involved in the biogenesis of most multi-pass membrane proteins in human cells. We are now focused on defining the molecular mechanisms underlying this process, using an interdisciplinary set of biochemical, structural, cell biological, genetic and bioinformatic approaches. These studies promise new insight into the fundamental biological challenge of membrane protein biogenesis.