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Mechanisms by Which Lipids Influence Conformational Dynamics of the GlpG Intramembrane Protease

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    Mechanisms by Which Lipids Influence Conformational Dynamics of the GlpG Intramembrane Protease
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    The Journal of Physical Chemistry B

    Cite this: J. Phys. Chem. B 2019, 123, 19, 4159–4172
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    https://doi.org/10.1021/acs.jpcb.8b11291
    Published May 6, 2019
    Copyright © 2019 American Chemical Society
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    Abstract

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    Rhomboid intramembrane proteases are bound to lipid membranes, where they dock and cleave other transmembrane substrates. How the lipid membrane surrounding the protease impacts the conformational dynamics of the protease is essential to understand because it informs on the reaction coordinate of substrate binding. Atomistic molecular dynamics simulations allow us to probe protein motions and characterize the coupling between protein and lipids. Simulations performed here on GlpG, the rhomboid protease from Escherichia coli, indicate that the thickness of the lipid membrane close to GlpG depends on both the composition of the lipid membrane and the conformation of GlpG. Transient binding of a lipid headgroup at the active site of the protease, as observed in some of the simulations reported here, suggests that a lipid headgroup might compete with the substrate for access to the GlpG active site. Interactions identified between lipid headgroups and the protein influence the dynamics of lipid interactions close to the substrate-binding site. These observations suggest that the lipid membrane environment shapes the energy profile of the substrate-docking region of the enzyme reaction coordinate.

    Copyright © 2019 American Chemical Society

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcb.8b11291.

    • Average values for selected H-bond distances; Cα rmsd profiles decomposed for the transmembrane segments vs loops and termini; Cα rmsd profiles for loops L1, L4, and L5; molecular graphics of overlaps between structure snapshots from each Sim; molecular graphics illustrating crystal structure waters; time series of the number of water molecules close to S201; time series of the distance between S201 and H254; time series of the number of lipid atoms within H-bond distance of selected protein groups in Sim1–Sim5, Sim1a, Sim1b, and in Sim6–Sim11, Sim6b, Sim7b; number of lipid N atoms within H-bond distance of D116; number of lipid phosphate oxygen atoms within H-bond distance of S147 and S248; illustration of lipid interactions in POPE and POPE/POPG membranes; dynamics of the cap loop L5 in K191A; molecular graphics of lipid/protein interactions in crystal structures; analyses of lipid interactions in Sims on wild type and D243A GlpG embedded in POPE; analyses of lipid interactions in Sims with GlpG embedded in POPC, DOPC, or DMPC; analyses of the cap loop in D243A (PDF)

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    This article is cited by 12 publications.

    1. Yasser Almeida-Hernandez, Henning Tidow. Soluble Regions of GlpG Influence Protein–Lipid Interactions and Lipid Distribution. The Journal of Physical Chemistry B 2019, 123 (37) , 7852-7858. https://doi.org/10.1021/acs.jpcb.9b06943
    2. Yannick Weyer, David Teis. The Dsc complex and its role in Golgi quality control. Biochemical Society Transactions 2024, 52 (5) , 2023-2034. https://doi.org/10.1042/BST20230375
    3. Swantje Mohr, Yessenbek K. Aldakul, Han Sun, Henry Sawczyc, Adam Lange. Mechanistic Studies of Membrane Proteins Using Integrated Solid-state NMR and Computational Approaches. 2023, 268-300. https://doi.org/10.1039/BK9781837670154-00268
    4. Oskar Engberg, David Ulbricht, Viola Döbel, Verena Siebert, Christian Frie, Anja Penk, Marius K. Lemberg, Daniel Huster. Rhomboid-catalyzed intramembrane proteolysis requires hydrophobic matching with the surrounding lipid bilayer. Science Advances 2022, 8 (38) https://doi.org/10.1126/sciadv.abq8303
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    6. Konstantina Karathanou, Ana-Nicoleta Bondar. Algorithm to catalogue topologies of dynamic lipid hydrogen-bond networks. Biochimica et Biophysica Acta (BBA) - Biomembranes 2022, 1864 (4) , 183859. https://doi.org/10.1016/j.bbamem.2022.183859
    7. Ana-Nicoleta Bondar. Phosphatidylglyerol Lipid Binding at the Active Site of an Intramembrane Protease. The Journal of Membrane Biology 2020, 253 (6) , 563-576. https://doi.org/10.1007/s00232-020-00152-z
    8. Ljubica Mihaljević, Siniša Urban. Decoding the Functional Evolution of an Intramembrane Protease Superfamily by Statistical Coupling Analysis. Structure 2020, 28 (12) , 1329-1336.e4. https://doi.org/10.1016/j.str.2020.07.015
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    10. Michalis Lazaratos, Konstantina Karathanou, Ana-Nicoleta Bondar. Graphs of dynamic H-bond networks: from model proteins to protein complexes in cell signaling. Current Opinion in Structural Biology 2020, 64 , 79-87. https://doi.org/10.1016/j.sbi.2020.06.006
    11. Robyn Stix, Chul-Jin Lee, José D. Faraldo-Gómez, Anirban Banerjee. Structure and Mechanism of DHHC Protein Acyltransferases. Journal of Molecular Biology 2020, 432 (18) , 4983-4998. https://doi.org/10.1016/j.jmb.2020.05.023
    12. Robyn Stix, James Song, Anirban Banerjee, José D. Faraldo-Gómez. DHHC20 Palmitoyl-Transferase Reshapes the Membrane to Foster Catalysis. Biophysical Journal 2020, 118 (4) , 980-988. https://doi.org/10.1016/j.bpj.2019.11.003
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    The Journal of Physical Chemistry B

    Cite this: J. Phys. Chem. B 2019, 123, 19, 4159–4172
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jpcb.8b11291
    Published May 6, 2019
    Copyright © 2019 American Chemical Society
    Request reuse permissions

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