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Molecular code for transmembrane-helix recognition by the Sec61 translocon

Abstract

Transmembrane α-helices in integral membrane proteins are recognized co-translationally and inserted into the membrane of the endoplasmic reticulum by the Sec61 translocon. A full quantitative description of this phenomenon, linking amino acid sequence to membrane insertion efficiency, is still lacking. Here, using in vitro translation of a model protein in the presence of dog pancreas rough microsomes to analyse a large number of systematically designed hydrophobic segments, we present a quantitative analysis of the position-dependent contribution of all 20 amino acids to membrane insertion efficiency, as well as of the effects of transmembrane segment length and flanking amino acids. The emerging picture of translocon-mediated transmembrane helix assembly is simple, with the critical sequence characteristics mirroring the physical properties of the lipid bilayer.

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Figure 1: The Lep model protein.
Figure 2: Position-specific contributions.
Figure 3: Length dependence of .
Figure 4: Distributions of values in natural proteins.

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Acknowledgements

We thank E. Missioux for technical assistance, and A. Elofsson and E. Lindahl for discussions. This work was supported by grants from the Swedish Foundation for Strategic Research, the Marianne and Marcus Wallenberg Foundation, the Swedish Cancer Foundation, the Swedish Research Council and the European Commission (BioSapiens) to G.v.H., the Magnus Bergvall Foundation to I.N., the National Institute of General Medical Sciences to S.H.W., the Swiss National Science Foundation to M.L.-B., and the Japan Society for the Promotion of Science to Y.S.

Author Contributions T.H. and N.M.M.-B. performed the experimental work together with H.K., Y.S., M.L.-B. and I.N. A.B. performed the computational work. T.H., N.M.M.-B., A.B., S.H.W. and G.v.H. prepared the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Gunnar von Heijne.

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The file contains Supplementary Figures S1-S6 with Legends and Supplementary Tables S1-S2. (PDF 715 kb)

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Hessa, T., Meindl-Beinker, N., Bernsel, A. et al. Molecular code for transmembrane-helix recognition by the Sec61 translocon. Nature 450, 1026–1030 (2007). https://doi.org/10.1038/nature06387

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