期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 134, 期 33, 页码 13700-13707出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja3034526
关键词
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资金
- U.S. Office of Naval Research (USONR) [N00014-10-1-0884]
- Department of Energy [DE-SC0006598]
- Alfred P. Sloan Foundation
- National Institute of General Medical Sciences [RC2GM093307]
- National Science Foundation [CHE-1040558]
- U.S. Department of Energy (DOE) [DE-SC0006598] Funding Source: U.S. Department of Energy (DOE)
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [1040558] Funding Source: National Science Foundation
Direct simulations reveal key mechanistic features of early-stage protein translocation and membrane integration via the Sec-translocon channel. We present a novel computational protocol that combines non-equilibrium growth of the nascent protein with microsecond timescale molecular dynamics trajectories. Analysis of multiple, long timescale simulations elucidates molecular features of protein insertion into the translocon, including signal-peptide docking at the translocon lateral gate (LG), large lengthscale conformational rearrangement of the translocon LG helices, and partial membrane integration of hydrophobic nascent-protein sequences. Furthermore, the simulations demonstrate the role of specific molecular interactions in the regulation of protein secretion, membrane integration, and integral membrane protein topology. Salt-bridge contacts between the nascent-protein N-terminus, cytosolic translocon residues, and phospholipid head groups are shown to favor conformations of the nascent protein upon early-stage insertion that are consistent with the Type II (N-cyt/C-exo) integral membrane protein topology, and extended hydrophobic contacts between the nascent protein and the membrane lipid bilayer are shown to stabilize configurations that are consistent with the Type III (N-exo/C-cyt) topology. These results provide a detailed, mechanistic basis for understanding experimentally observed correlations between integral membrane protein topology, translocon mutagenesis, and nascent-protein sequence.
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