Journal Article

FZJ-2019-05106

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The Membrane-Integrated Steric Chaperone Lif Facilitates Active Site Opening of Pseudomonas aeruginosa Lipase A

Verma, N. ; Dollinger, P. ; Kovacic, F.FZJ* ; Jaeger, K.-E.FZJ* ; Gohlke, H. (Corresponding author)FZJ*

2020
Wiley New York, NY [u.a.]

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Please use a persistent id in citations: http://hdl.handle.net/2128/24021  doi:10.1002/jcc.26085

Abstract: Lipases 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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Contributing Institute(s):

1. John von Neumann - Institut für Computing (NIC)
2. Jülich Supercomputing Center (JSC)
3. Strukturbiochemie (ICS-6)
4. Institut für Molekulare Enzymtechnologie (HHUD) (IMET)

Research Program(s):

1. 511 - Computational Science and Mathematical Methods (POF3-511) (POF3-511)
2. Forschergruppe Gohlke (hkf7_20170501) (hkf7_20170501)
3. Analysis of the conformational changes during activation of lipase A by its foldase (hdd16_20171101) (hdd16_20171101)
4. Conformational dynamics of the unbound lipase-specific foldase Lif (hdd16_20161101) (hdd16_20161101)

Appears in the scientific report 2020

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Database coverage:
; ; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; Ebsco Academic Search ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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