Regulation of multispanning membrane protein topology via post-translational annealing

  1. Reid C Van Lehn
  2. Bin Zhang
  3. Thomas F Miller  Is a corresponding author
  1. California Institute of Technology, United States

Abstract

The canonical mechanism for multispanning membrane protein topogenesis suggests that protein topology is established during cotranslational membrane integration. However, this mechanism is inconsistent with the behavior of EmrE, a dual-topology protein for which the mutation of positively charged loop residues, even close to the C-terminus, leads to dramatic shifts in its topology. We use coarse-grained simulations to investigate the Sec-facilitated membrane integration of EmrE and its mutants on realistic biological timescales. This work reveals a mechanism for regulating membrane-protein topogenesis, in which initially misintegrated configurations of the proteins undergo post-translational annealing to reach fully integrated multispanning topologies. The energetic barriers associated with this post-translational annealing process enforce kinetic pathways that dictate the topology of the fully integrated proteins. The proposed mechanism agrees well with the experimentally observed features of EmrE topogenesis and provides a range of experimentally testable predictions regarding the effect of translocon mutations on membrane protein topogenesis.

Article and author information

Author details

  1. Reid C Van Lehn

    Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Bin Zhang

    Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Thomas F Miller

    Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, United States
    For correspondence
    tfm@caltech.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Gerhard Hummer, The Max Planck Institute of Biophysics, Germany

Publication history

  1. Received: May 14, 2015
  2. Accepted: September 25, 2015
  3. Accepted Manuscript published: September 26, 2015 (version 1)
  4. Version of Record published: November 6, 2015 (version 2)

Copyright

© 2015, Van Lehn et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Reid C Van Lehn
  2. Bin Zhang
  3. Thomas F Miller
(2015)
Regulation of multispanning membrane protein topology via post-translational annealing
eLife 4:e08697.
https://doi.org/10.7554/eLife.08697

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