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Published October 25, 2012 | Supplemental Material + Published
Journal Article Open

Long-Timescale Dynamics and Regulation of Sec-Facilitated Protein Translocation

Abstract

We present a coarse-grained modeling approach that spans the nanosecond- to minute-timescale dynamics of cotranslational protein translocation. The method enables direct simulation of both integral membrane protein topogenesis and transmembrane domain (TM) stop-transfer efficiency. Simulations reveal multiple kinetic pathways for protein integration, including a mechanism in which the nascent protein undergoes slow-timescale reorientation, or flipping, in the confined environment of the translocon channel. Competition among these pathways gives rise to the experimentally observed dependence of protein topology on ribosomal translation rate and protein length. We further demonstrate that sigmoidal dependence of stop-transfer efficiency on TM hydrophobicity arises from local equilibration of the TM across the translocon lateral gate, and it is predicted that slowing ribosomal translation yields decreased stop-transfer efficiency in long proteins. This work reveals the balance between equilibrium and nonequilibrium processes in protein targeting, and it provides insight into the molecular regulation of the Sec translocon.

Additional Information

© 2012 The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 Unported License (CC-BY-NC-ND; http://creativecommons.org/licenses/by-nc-nd/3.0/ legalcode). Received: March 30, 2012. Revised: July 21, 2012. Accepted: August 31, 2012. Published online: October 18, 2012. This research was supported in part by the U.S. Office of Naval Research (USONR) under Grant No. N00014-10-1-0884, and T.F.M. acknowledges an Alfred P. Sloan Foundation fellowship. Computational resources were provided by the National Energy Research Scientific Computing Center, which is supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231, and by the National Science Foundation under Grant No. CHE-1040558. We additionally acknowledge use of the Anton super-computer system that is hosted by the National Resource for Biomedical Supercomputing (NRBSC) at the Pittsburgh Supercomputing Center (PSC), with funding from the National Institute of General Medical Sciences under grant RC2GM093307.

Attached Files

Published - PIIS221112471200280X.pdf

Supplemental Material - DocumentS1.pdf

Supplemental Material - DocumentS2.pdf

Supplemental Material - MovieS1.mp4

Supplemental Material - MovieS2.mp4

Supplemental Material - MovieS3.mp4

Supplemental Material - MovieS4.mp4

Supplemental Material - MovieS5.mp4

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Additional details

Created:
August 19, 2023
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October 19, 2023