Regulation of multispanning membrane protein topology via post-translational annealing

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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.

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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.
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.
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.

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