This title appears in the Scientific Report :
2020
Please use the identifier:
http://dx.doi.org/10.1002/jcc.26085 in citations.
Please use the identifier: http://hdl.handle.net/2128/24021 in citations.
The Membrane-Integrated Steric Chaperone Lif Facilitates Active Site Opening of Pseudomonas aeruginosa Lipase A
The Membrane-Integrated Steric Chaperone Lif Facilitates Active Site Opening of Pseudomonas aeruginosa Lipase A
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 r...
Saved in:
Personal Name(s): | Verma, Neha |
---|---|
Dollinger, Peter / Kovacic, Filip / Jaeger, Karl-Erich / Gohlke, Holger (Corresponding author) | |
Contributing Institute: |
Institut für Molekulare Enzymtechnologie (HHUD); IMET Strukturbiochemie; ICS-6 Jülich Supercomputing Center; JSC John von Neumann - Institut für Computing; NIC |
Published in: | Journal of computational chemistry, 4 (2020) 6, S. 500-512 |
Imprint: |
New York, NY [u.a.]
Wiley
2020
|
DOI: |
10.1002/jcc.26085 |
PubMed ID: |
31618459 |
Document Type: |
Journal Article |
Research Program: |
Conformational dynamics of the unbound lipase-specific foldase Lif Analysis of the conformational changes during activation of lipase A by its foldase Forschergruppe Gohlke Computational Science and Mathematical Methods |
Link: |
Restricted Published on 2019-10-16. Available in OpenAccess from 2020-10-16. Published on 2019-10-16. Available in OpenAccess from 2020-10-16. Restricted |
Publikationsportal JuSER |
Please use the identifier: http://hdl.handle.net/2128/24021 in citations.
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. |