Article | Published:

A topological and conformational stability alphabet for multipass membrane proteins

Nature Chemical Biology volume 12, pages 167173 (2016) | Download Citation

Abstract

Multipass membrane proteins perform critical signal transduction and transport across membranes. How transmembrane helix (TMH) sequences encode the topology and conformational flexibility regulating these functions remains poorly understood. Here we describe a comprehensive analysis of the sequence-structure relationships at multiple interacting TMHs from all membrane proteins with structures in the Protein Data Bank (PDB). We found that membrane proteins can be deconstructed in interacting TMH trimer units, which mostly fold into six distinct structural classes of topologies and conformations. Each class is enriched in recurrent sequence motifs from functionally unrelated proteins, revealing unforeseen consensus and evolutionary conserved networks of stabilizing interhelical contacts. Interacting TMHs' topology and local protein conformational flexibility were remarkably well predicted in a blinded fashion from the identified binding-hotspot motifs. Our results reveal universal sequence-structure principles governing the complex anatomy and plasticity of multipass membrane proteins that may guide de novo structure prediction, design, and studies of folding and dynamics.

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Acknowledgements

We thank the members of the Barth laboratory for insightful discussions during this study and critical comments on the manuscript. This work was supported by a grant from the US National Institute of Health (1R01GM097207-01A1) and by a supercomputer allocation from XSEDE (Extreme Science and Engineering Discovery Environment; MCB120101) to P.B.

Author information

Affiliations

  1. Department of Pharmacology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA.

    • Xiang Feng
    •  & Patrick Barth
  2. Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.

    • Patrick Barth
  3. Structural and Computational Biology and Molecular Biophysics Graduate Program, Baylor College of Medicine, Houston, Texas, USA.

    • Patrick Barth

Authors

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Contributions

P.B. designed the study; X.F. performed the study; P.B. and X.F. analyzed and discussed the results; P.B. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Patrick Barth.

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    Supplementary Text and Figures

    Supplementary Results, Supplementary Figures 1–5 and Supplementary Tables 1–6.

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DOI

https://doi.org/10.1038/nchembio.2001

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