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Engineering cardiolipin binding to an artificial membrane protein reveals determinants for lipid-mediated stabilization

ML. Abramsson, RA. Corey, JL. Skerle, LJ. Persson, O. Anden, AO. Oluwole, RJ. Howard, E. Lindahl, CV. Robinson, K. Strisovsky, EG. Marklund, D. Drew, PJ. Stansfeld, M. Landreh

. 2025 ; 14 (-) : . [pub] 20250430

Language English Country England, Great Britain

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc25016012

Grant support
InterCOST programme (project no. LUC23180) Ministerstvo Školství, Mládeže a Tělovýchovy
2019-02433 Vetenskapsrådet
BB/P01948X/1 Biotechnology and Biological Sciences Research Council - United Kingdom
Consolidator Grant Svenska Sällskapet för Medicinsk Forskning
2020- 04825 Swedish Research Council
BB/S003339/1 Biotechnology and Biological Sciences Research Council - United Kingdom
Operational Programme CZ.02.1.01/0.0/0.0/16_019/0000729 European Regional Development Fund
10.35802/208361 Wellcome Trust - United Kingdom
2021-05806 Vetenskapsrådet
BB/Y003187/1 Biotechnology and Biological Sciences Research Council - United Kingdom
2019-01961 Vetenskapsrådet
MR/V028839/1 Medical Research Council - United Kingdom
22-2023 Pj Cancerfonden
MR/S009213/1 Medical Research Council - United Kingdom
Wellcome Trust - United Kingdom

Integral membrane proteins carry out essential functions in the cell, and their activities are often modulated by specific protein-lipid interactions in the membrane. Here, we elucidate the intricate role of cardiolipin (CDL), a regulatory lipid, as a stabilizer of membrane proteins and their complexes. Using the in silico-designed model protein TMHC4_R (ROCKET) as a scaffold, we employ a combination of molecular dynamics simulations and native mass spectrometry to explore the protein features that facilitate preferential lipid interactions and mediate stabilization. We find that the spatial arrangement of positively charged residues as well as local conformational flexibility are factors that distinguish stabilizing from non-stabilizing CDL interactions. However, we also find that even in this controlled, artificial system, a clear-cut distinction between binding and stabilization is difficult to attain, revealing that overlapping lipid contacts can partially compensate for the effects of binding site mutations. Extending our insights to naturally occurring proteins, we identify a stabilizing CDL site within the E. coli rhomboid intramembrane protease GlpG and uncover its regulatory influence on enzyme substrate preference. In this work, we establish a framework for engineering functional lipid interactions, paving the way for the design of proteins with membrane-specific properties or functions.

References provided by Crossref.org

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$a Anden, Olivia $u Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University, Solna, Sweden
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$a Howard, Rebecca J $u Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University, Solna, Sweden $1 https://orcid.org/0000000320493378
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