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| Hauptverfasser: | , , , , , , , , , , , |
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| Format: | Artículo científico |
| Sprache: | en |
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Nature communications
2025
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| Schlagworte: | |
| Online-Zugang: | https://pubmed.ncbi.nlm.nih.gov/40016208/ |
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Inhaltsangabe:
- Kingdom-specific lipid unsaturation calibrates sequence evolution in membrane arm subunits of eukaryotic respiratory complexes. Gupta, Pooja Chakroborty, Sristi Rathod, Arun K Kumar, K Ranjith Bhat, Shreya Ghosh, Suparna Rao T, Pallavi Yele, Kameshwari Bakthisaran, Raman Nagaraj, R Manna, Moutusi Raychaudhuri, Swasti Humans Evolution, Molecular Molecular Dynamics Simulation Arabidopsis Mitochondrial Membranes Electron Transport Complex I Cardiolipins Protein Subunits Mutation Lipids Amino Acid Sequence Sequence evolution of protein complexes (PCs) is constrained by protein-protein interactions (PPIs). PPI-interfaces are predominantly conserved and hotspots for disease-related mutations. How do lipid-protein interactions (LPIs) constrain sequence evolution of membrane-PCs? We explore Respiratory Complexes (RCs) as a case study as these allow to compare sequence evolution in subunits exposed to both lipids in inner-mitochondrial membrane (IMM) and lipid-free aqueous matrix. We find that lipid-exposed surfaces of the IMM-subunits but not of the matrix subunits are populated with non-PPI disease-causing mutations signifying LPIs in stabilizing RCs. Further, IMM-subunits including their exposed surfaces show high intra-kingdom sequence conservation but remarkably diverge beyond. Molecular Dynamics simulation suggests contrasting LPIs of structurally superimposable but sequence-wise diverged IMM-exposed helices of Complex I (CI) subunit Ndufa1 from human and Arabidopsis depending on kingdom-specific unsaturation of cardiolipin fatty acyl chains. in cellulo assays consolidate inter-kingdom incompatibility of Ndufa1-helices due to the lipid-exposed amino acids. Plant-specific unsaturated fatty acids in human cells also trigger CI-instability. Taken together, we posit that altered LPIs calibrate sequence evolution at the IMM-arms of eukaryotic RCs.