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Modeling the dynamics and regulation of Sec-facilitated protein translocation and membrane integration

Miller, Thomas F. (2013) Modeling the dynamics and regulation of Sec-facilitated protein translocation and membrane integration. In: 246th ACS National Meeting & Exposition, Sept. 8-12, 2013, Indianapolis, IN.

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We present a novel modeling approach that spans the nanosecond- to minute-timescale dynamics of co-translational protein translocation. Based on detailed all-atom simulations, 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 exptl. obsd. dependence of protein topol. 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 equil. and nonequil. processes in protein targeting, and it provides insight into the mol. regulation of the Sec translocon.

Item Type:Conference or Workshop Item (Paper)
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Miller, Thomas F.0000-0002-1882-5380
Additional Information:© 2013 American Chemical Society.
Record Number:CaltechAUTHORS:20131011-110351925
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:41892
Deposited By: Tony Diaz
Deposited On:11 Oct 2013 20:53
Last Modified:03 Oct 2019 05:53

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