Topological constraints and modular structure in the folding and functional motions of GlpG, an intramembrane protease

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearch

Standard

Topological constraints and modular structure in the folding and functional motions of GlpG, an intramembrane protease. / Schafer, Nicholas; Truong, Ha H; Otzen, Daniel; Lindorff-Larsen, Kresten; Wolynes, Peter G.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 8, 2016, p. 2098-2103.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearch

Harvard

Schafer, N, Truong, HH, Otzen, D, Lindorff-Larsen, K & Wolynes, PG 2016, 'Topological constraints and modular structure in the folding and functional motions of GlpG, an intramembrane protease', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 8, pp. 2098-2103. https://doi.org/10.1073/pnas.1524027113

APA

Schafer, N., Truong, H. H., Otzen, D., Lindorff-Larsen, K., & Wolynes, P. G. (2016). Topological constraints and modular structure in the folding and functional motions of GlpG, an intramembrane protease. Proceedings of the National Academy of Sciences of the United States of America, 113(8), 2098-2103. https://doi.org/10.1073/pnas.1524027113

CBE

Schafer N, Truong HH, Otzen D, Lindorff-Larsen K, Wolynes PG. 2016. Topological constraints and modular structure in the folding and functional motions of GlpG, an intramembrane protease. Proceedings of the National Academy of Sciences of the United States of America. 113(8):2098-2103. https://doi.org/10.1073/pnas.1524027113

MLA

Schafer, Nicholas et al. "Topological constraints and modular structure in the folding and functional motions of GlpG, an intramembrane protease". Proceedings of the National Academy of Sciences of the United States of America. 2016, 113(8). 2098-2103. https://doi.org/10.1073/pnas.1524027113

Vancouver

Schafer N, Truong HH, Otzen D, Lindorff-Larsen K, Wolynes PG. Topological constraints and modular structure in the folding and functional motions of GlpG, an intramembrane protease. Proceedings of the National Academy of Sciences of the United States of America. 2016;113(8):2098-2103. https://doi.org/10.1073/pnas.1524027113

Author

Schafer, Nicholas ; Truong, Ha H ; Otzen, Daniel ; Lindorff-Larsen, Kresten ; Wolynes, Peter G. / Topological constraints and modular structure in the folding and functional motions of GlpG, an intramembrane protease. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 8. pp. 2098-2103.

Bibtex

@article{6486ac2c1aeb4055b8c1fd7f807240eb,
title = "Topological constraints and modular structure in the folding and functional motions of GlpG, an intramembrane protease",
abstract = "We investigate the folding of GlpG, an intramembrane protease, using perfectly funneled structure-based models that implicitly account for the absence or presence of the membrane. These two models are used to describe, respectively, folding in detergent micelles and folding within a bilayer, which effectively constrains GlpG's topology in unfolded and partially folded states. Structural free-energy landscape analysis shows that although the presence of multiple folding pathways is an intrinsic property of GlpG's modular functional architecture, the large entropic cost of organizing helical bundles in the absence of the constraining bilayer leads to pathways that backtrack (i.e., local unfolding of previously folded substructures is required when moving from the unfolded to the folded state along the minimum free-energy pathway). This backtracking explains the experimental observation of thermodynamically destabilizing mutations that accelerate GlpG's folding in detergent micelles. In contrast, backtracking is absent from the model when folding is constrained within a bilayer, the environment in which GlpG has evolved to fold. We also characterize a near-native state with a highly mobile transmembrane helix 5 (TM5) that is significantly populated under folding conditions when GlpG is embedded in a bilayer. Unbinding of TM5 from the rest of the structure exposes GlpG's active site, consistent with studies of the catalytic mechanism of GlpG that suggest that TM5 serves as a substrate gate to the active site.",
author = "Nicholas Schafer and Truong, {Ha H} and Daniel Otzen and Kresten Lindorff-Larsen and Wolynes, {Peter G}",
year = "2016",
doi = "10.1073/pnas.1524027113",
language = "English",
volume = "113",
pages = "2098--2103",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "The National Academy of Sciences of the United States of America",
number = "8",

}

RIS

TY - JOUR

T1 - Topological constraints and modular structure in the folding and functional motions of GlpG, an intramembrane protease

AU - Schafer, Nicholas

AU - Truong, Ha H

AU - Otzen, Daniel

AU - Lindorff-Larsen, Kresten

AU - Wolynes, Peter G

PY - 2016

Y1 - 2016

N2 - We investigate the folding of GlpG, an intramembrane protease, using perfectly funneled structure-based models that implicitly account for the absence or presence of the membrane. These two models are used to describe, respectively, folding in detergent micelles and folding within a bilayer, which effectively constrains GlpG's topology in unfolded and partially folded states. Structural free-energy landscape analysis shows that although the presence of multiple folding pathways is an intrinsic property of GlpG's modular functional architecture, the large entropic cost of organizing helical bundles in the absence of the constraining bilayer leads to pathways that backtrack (i.e., local unfolding of previously folded substructures is required when moving from the unfolded to the folded state along the minimum free-energy pathway). This backtracking explains the experimental observation of thermodynamically destabilizing mutations that accelerate GlpG's folding in detergent micelles. In contrast, backtracking is absent from the model when folding is constrained within a bilayer, the environment in which GlpG has evolved to fold. We also characterize a near-native state with a highly mobile transmembrane helix 5 (TM5) that is significantly populated under folding conditions when GlpG is embedded in a bilayer. Unbinding of TM5 from the rest of the structure exposes GlpG's active site, consistent with studies of the catalytic mechanism of GlpG that suggest that TM5 serves as a substrate gate to the active site.

AB - We investigate the folding of GlpG, an intramembrane protease, using perfectly funneled structure-based models that implicitly account for the absence or presence of the membrane. These two models are used to describe, respectively, folding in detergent micelles and folding within a bilayer, which effectively constrains GlpG's topology in unfolded and partially folded states. Structural free-energy landscape analysis shows that although the presence of multiple folding pathways is an intrinsic property of GlpG's modular functional architecture, the large entropic cost of organizing helical bundles in the absence of the constraining bilayer leads to pathways that backtrack (i.e., local unfolding of previously folded substructures is required when moving from the unfolded to the folded state along the minimum free-energy pathway). This backtracking explains the experimental observation of thermodynamically destabilizing mutations that accelerate GlpG's folding in detergent micelles. In contrast, backtracking is absent from the model when folding is constrained within a bilayer, the environment in which GlpG has evolved to fold. We also characterize a near-native state with a highly mobile transmembrane helix 5 (TM5) that is significantly populated under folding conditions when GlpG is embedded in a bilayer. Unbinding of TM5 from the rest of the structure exposes GlpG's active site, consistent with studies of the catalytic mechanism of GlpG that suggest that TM5 serves as a substrate gate to the active site.

U2 - 10.1073/pnas.1524027113

DO - 10.1073/pnas.1524027113

M3 - Journal article

C2 - 26858402

VL - 113

SP - 2098

EP - 2103

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 8

ER -