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000865808 1001_ $$0P:(DE-HGF)0$$aVerma, Neha$$b0
000865808 245__ $$aThe Membrane-Integrated Steric Chaperone Lif Facilitates Active Site Opening of Pseudomonas aeruginosa Lipase A
000865808 260__ $$aNew York, NY [u.a.]$$bWiley$$c2020
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000865808 520__ $$aLipases are essential and widely used biocatalysts. Hence, the production of lipases requires a detailed understanding of the molecular mechanism of its folding and secretion. Lipase A from Pseudomonas aeruginosa, PaLipA, constitutes a prominent example that has additional relevance because of its role as a virulence factor in many diseases. PaLipA requires the assistance of a membrane‐integrated steric chaperone, the lipase‐specific foldase Lif, to achieve its enzymatically active state. However, the molecular mechanism of how Lif activates its cognate lipase has remained elusive. Here, we show by molecular dynamics simulations at the atomistic level and potential of mean force computations that Lif catalyzes the activation process of PaLipA by structurally stabilizing an intermediate PaLipA conformation, particularly a β‐sheet in the region of residues 17–30, such that the opening of PaLipA's lid domain is facilitated. This opening allows substrate access to PaLipA's catalytic site. A surprising and so far not fully understood aspect of our study is that the open state of PaLipA is unstable compared to the closed one according to our computational and in vitro biochemical results. We thus speculate that further interactions of PaLipA with the Xcp secretion machinery and/or components of the extracellular matrix contribute to the remaining activity of secreted PaLipA.
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000865808 536__ $$0G:(DE-Juel1)hdd16_20171101$$aAnalysis of the conformational changes during activation of lipase A by its foldase (hdd16_20171101)$$chdd16_20171101$$fAnalysis of the conformational changes during activation of lipase A by its foldase$$x2
000865808 536__ $$0G:(DE-Juel1)hdd16_20161101$$aConformational dynamics of the unbound lipase-specific foldase Lif (hdd16_20161101)$$chdd16_20161101$$fConformational dynamics of the unbound lipase-specific foldase Lif$$x3
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000865808 7001_ $$0P:(DE-HGF)0$$aDollinger, Peter$$b1
000865808 7001_ $$0P:(DE-Juel1)131480$$aKovacic, Filip$$b2
000865808 7001_ $$0P:(DE-Juel1)131457$$aJaeger, Karl-Erich$$b3
000865808 7001_ $$0P:(DE-Juel1)172663$$aGohlke, Holger$$b4$$eCorresponding author
000865808 773__ $$0PERI:(DE-600)1479181-x$$a10.1002/jcc.26085$$n6$$p500-512$$tJournal of computational chemistry$$v4$$x0192-8651$$y2020
000865808 8564_ $$uhttps://juser.fz-juelich.de/record/865808/files/Verma_et_al-2020-Journal_of_Computational_Chemistry.pdf$$yRestricted
000865808 8564_ $$uhttps://juser.fz-juelich.de/record/865808/files/PMF_LifLipA_manuscript_final_rev2_final.pdf$$yPublished on 2019-10-16. Available in OpenAccess from 2020-10-16.
000865808 8564_ $$uhttps://juser.fz-juelich.de/record/865808/files/PMF_LifLipA_manuscript_final_rev2_final.pdf?subformat=pdfa$$xpdfa$$yPublished on 2019-10-16. Available in OpenAccess from 2020-10-16.
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