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Nat Chem Biol. 2016 Mar;12(3):167-73. doi: 10.1038/nchembio.2001. Epub 2016 Jan 18.

A topological and conformational stability alphabet for multipass membrane proteins.

Feng X1, Barth P1,2,3.

Author information

1
Department of Pharmacology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA.
2
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.
3
Structural and Computational Biology and Molecular Biophysics Graduate Program, Baylor College of Medicine, Houston, Texas, USA.

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.

PMID:
26780406
PMCID:
PMC6495056
DOI:
10.1038/nchembio.2001
[Indexed for MEDLINE]
Free PMC Article

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