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A topological and conformational stability alphabet for multipass membrane proteins

Nature Chemical Biology volume 12, pages 167–173 (2016)Cite this article

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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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Figure 1: TMH trimers cluster in six major structure classes with enriched sequence motifs.
Figure 2: Recurrent sequence motifs create consensus interhelical trimer interactions across protein families.
Figure 3: Consensus patterns of contacts display unique combinations of atomic interactions.
Figure 4: Sequence motifs create evolutionary conserved networks of interhelical stabilizing contacts.
Figure 5: Sequence−3D contact motifs are strong predictors of local conformational stability.

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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.

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Authors and 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

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  1. Xiang Feng
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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.

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Correspondence to Patrick Barth.

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The authors declare no competing financial interests.

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Supplementary Results, Supplementary Figures 1–5 and Supplementary Tables 1–6. (PDF 6180 kb)

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Feng, X., Barth, P. A topological and conformational stability alphabet for multipass membrane proteins. Nat Chem Biol 12, 167–173 (2016). https://doi.org/10.1038/nchembio.2001

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