Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis.,Chemical Reviews

当前位置： X-MOL 学术 › Chem. Rev. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis.
Chemical Reviews ( IF 51.4 ) Pub Date : 2019-01-04 , DOI: 10.1021/acs.chemrev.8b00532
Justin T Marinko _{1,

2} , Hui Huang _{1,

2} , Wesley D Penn ₃ , John A Capra _{2,

4} , Jonathan P Schlebach ₃ , Charles R Sanders ₁

Affiliation

Advances over the past 25 years have revealed much about how the structural properties of membranes and associated proteins are linked to the thermodynamics and kinetics of membrane protein (MP) folding. At the same time biochemical progress has outlined how cellular proteostasis networks mediate MP folding and manage misfolding in the cell. When combined with results from genomic sequencing, these studies have established paradigms for how MP folding and misfolding are linked to the molecular etiologies of a variety of diseases. This emerging framework has paved the way for the development of a new class of small molecule "pharmacological chaperones" that bind to and stabilize misfolded MP variants, some of which are now in clinical use. In this review, we comprehensively outline current perspectives on the folding and misfolding of integral MPs as well as the mechanisms of cellular MP quality control. Based on these perspectives, we highlight new opportunities for innovations that bridge our molecular understanding of the energetics of MP folding with the nuanced complexity of biological systems. Given the many linkages between MP misfolding and human disease, we also examine some of the exciting opportunities to leverage these advances to address emerging challenges in the development of therapeutics and precision medicine.

中文翻译：

健康和疾病中人膜蛋白的折叠和错误折叠：从单分子到细胞蛋白质稳态。

过去 25 年的进展揭示了膜和相关蛋白的结构特性如何与膜蛋白 (MP) 折叠的热力学和动力学相关的很多内容。与此同时，生化进展概述了细胞蛋白质稳态网络如何介导 MP 折叠和管理细胞中的错误折叠。与基因组测序结果相结合，这些研究已经建立了 MP 折叠和错误折叠如何与多种疾病的分子病因学相关的范例。这一新兴框架为开发一类新型小分子“药理学伴侣”铺平了道路，这些小分子“药理学伴侣”可以结合并稳定错误折叠的 MP 变体，其中一些现已投入临床使用。在这篇综述中，我们全面概述了当前关于完整 MP 的折叠和错误折叠以及细胞 MP 质量控制机制的观点。基于这些观点，我们强调了新的创新机会，将我们对 MP 折叠能量学的分子理解与生物系统的微妙复杂性联系起来。鉴于MP错误折叠与人类疾病之间存在许多联系，我们还研究了一些令人兴奋的机会，以利用这些进展来应对治疗学和精准医学发展中新出现的挑战。

更新日期：2019-01-04

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11