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  • Perspective
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Cellular mechanisms of membrane protein folding

Nature Structural & Molecular Biology volume 16, pages 606–612 (2009)Cite this article

Abstract

The membrane protein–folding problem can be articulated by two central questions. How is protein topology established by selective peptide transport to opposite sides of the cellular membrane? And how are transmembrane segments inserted, integrated and folded within the lipid bilayer? In eukaryotes, this process usually takes place in the endoplasmic reticulum, coincident with protein synthesis, and is facilitated by the translating ribosome and the Sec61 translocon complex (RTC). At its core, the RTC forms a dynamic pathway through which the elongating nascent polypeptide moves as it is delivered into the cytosolic, lumenal and lipid compartments. This Perspective will focus on emerging evidence that the RTC functions as a protein-folding machine that restricts conformational space by establishing transmembrane topology and yet provides a permissive environment that enables nascent transmembrane domains to efficiently progress down their folding energy landscape.

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Figure 1: Models of polytopic protein biogenesis.
Figure 2: Mechanism of TM integration.
Figure 3: Potential arrangement of Sec61αβγ heterotrimers (gray cylinders) in the assembled translocon (purple disc) and implications for co-translational folding.

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Acknowledgements

I would like to thank B. Conti and other members of the Skach laboratory for helpful comments on this manuscript and the US National Institutes of Health (R01GM53457 and R01 DK51818) for supporting our research in this area.

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  1. William R Skach is in the Department of Biochemistry & Molecular Biology, Oregon Health & Sciences University, Portland, Oregon, USA.,

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Skach, W. Cellular mechanisms of membrane protein folding. Nat Struct Mol Biol 16, 606–612 (2009). https://doi.org/10.1038/nsmb.1600

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