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The safety dance: biophysics of membrane protein folding and misfolding in a cellular context

Published online by Cambridge University Press:  25 November 2014

Jonathan P. Schlebach  and
Charles R. Sanders
Jonathan P. Schlebach
Affiliation:
Department of Biochemistry and Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
Charles R. Sanders*
Affiliation:
Department of Biochemistry and Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
*
*Author for correspondence: C. R. Sanders, Department of Biochemistry and Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. Phone: 615-936-3756; Fax: 615-936-2211; Email: chuck.sanders@vanderbilt.edu
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Abstract

Most biological processes require the production and degradation of proteins, a task that weighs heavily on the cell. Mutations that compromise the conformational stability of proteins place both specific and general burdens on cellular protein homeostasis (proteostasis) in ways that contribute to numerous diseases. Efforts to elucidate the chain of molecular events responsible for diseases of protein folding address one of the foremost challenges in biomedical science. However, relatively little is known about the processes by which mutations prompt the misfolding of α-helical membrane proteins, which rely on an intricate network of cellular machinery to acquire and maintain their functional structures within cellular membranes. In this review, we summarize the current understanding of the physical principles that guide membrane protein biogenesis and folding in the context of mammalian cells. Additionally, we explore how pathogenic mutations that influence biogenesis may differ from those that disrupt folding and assembly, as well as how this may relate to disease mechanisms and therapeutic intervention. These perspectives indicate an imperative for the use of information from structural, cellular, and biochemical studies of membrane proteins in the design of novel therapeutics and in personalized medicine.

Type
Review Article
Information
Quarterly Reviews of Biophysics , Volume 48 , Issue 1 , February 2015 , pp. 1 - 34
Copyright
Copyright © Cambridge University Press 2014 

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