Recognition of transmembrane helices by the endoplasmic reticulum translocon


Membrane proteins depend on complex translocation machineries for insertion into target membranes. Although it has long been known that an abundance of nonpolar residues in transmembrane helices is the principal criterion for membrane insertion, the specific sequence-coding for transmembrane helices has not been identified. By challenging the endoplasmic reticulum Sec61 translocon with an extensive set of designed polypeptide segments, we have determined the basic features of this code, including a ‘biological’ hydrophobicity scale. We find that membrane insertion depends strongly on the position of polar residues within transmembrane segments, adding a new dimension to the problem of predicting transmembrane helices from amino acid sequences. Our results indicate that direct protein–lipid interactions are critical during translocon-mediated membrane insertion.

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Figure 1: Integration of H-segments into the microsomal membrane.
Figure 2: Biological and biophysical ΔGaa scales.
Figure 3: Positional dependencies in ΔGapp.


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We wish to thank E. Missioux for technical assistance and R. MacKinnon, D. Rees, and T. Rapoport for comments. This work was supported by grants from the Swedish Cancer Foundation to G.v.H. and I.M.N., the Marianne and Marcus Wallenberg Foundation and the Swedish Research Council to G.v.H., the Magnus Bergvall Foundation to I.M.N., and the National Institute of General Medical Sciences to S.H.W.

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Correspondence to Gunnar von Heijne.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Data S1

Derivation of the δGaaapp scale. (PDF 60 kb)

Supplementary Data S2

Additivity of δGaaapp values (PDF 58 kb)

Supplementary Data S3

H-segment constructs expressed in vivo. (PDF 73 kb)

Supplementary Data S4

H-segments used to analyse the role of flanking residues. (PDF 58 kb)

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Hessa, T., Kim, H., Bihlmaier, K. et al. Recognition of transmembrane helices by the endoplasmic reticulum translocon. Nature 433, 377–381 (2005).

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