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J Mol Biol. 2015 Mar 13;427(5):999-1022. doi: 10.1016/j.jmb.2014.09.014. Epub 2014 Sep 30.

Mechanisms of integral membrane protein insertion and folding.

Author information

Center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm.
Science for Life Laboratory Stockholm University, Box 1031, SE-171 21 Solna, Sweden.
Department of Physiology and Biophysics and the Center for Biomembrane Systems University of California, Irvine Irvine, CA 92697.
Contributed equally


The biogenesis, folding, and structure of α-helical membrane proteins (MPs) are important to understand because they underlie virtually all physiological processes in cells including key metabolic pathways, such as the respiratory chain and the photosystems, as well as the transport of solutes and signals across membranes. Nearly all MPs require translocons--often referred to as protein-conducting channels--for proper insertion into their target membrane. Remarkable progress toward understanding the structure and functioning of translocons has been made during the past decade. Here, we review and assess this progress critically. All available evidence indicates that MPs are equilibrium structures that achieve their final structural states by folding along thermodynamically controlled pathways. The main challenge for cells is the targeting and membrane insertion of highly hydrophobic amino acid sequences. Targeting and insertion are managed in cells principally by interactions between ribosomes and membrane-embedded translocons. Our review examines the biophysical and biological boundaries of MP insertion and the folding of polytopic MPs in vivo. A theme of the review is the under-appreciated role of basic thermodynamic principles in MP folding and assembly. Thermodynamics not only dictates the final folded structure but also is the driving force for the evolution of the ribosome-translocon system of assembly. We conclude the review with a perspective suggesting a new view of translocon-guided MP insertion.


lipid–protein interactions; membrane protein biogenesis; membrane protein folding; transmembrane helix

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