Kingdom-specific lipid unsaturation calibrates sequence evolution in membrane arm subunits of eukaryotic respiratory complexes
Abstract 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 Respi...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57295-7 |
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| author | Pooja Gupta Sristi Chakroborty Arun K. Rathod K. Ranjith Kumar Shreya Bhat Suparna Ghosh Pallavi Rao T Kameshwari Yele Raman Bakthisaran R. Nagaraj Moutusi Manna Swasti Raychaudhuri |
| author_facet | Pooja Gupta Sristi Chakroborty Arun K. Rathod K. Ranjith Kumar Shreya Bhat Suparna Ghosh Pallavi Rao T Kameshwari Yele Raman Bakthisaran R. Nagaraj Moutusi Manna Swasti Raychaudhuri |
| author_sort | Pooja Gupta |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-a40fdda397374745841d50e78f0d91cf |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-a40fdda397374745841d50e78f0d91cf2025-08-20T03:04:34ZengNature PortfolioNature Communications2041-17232025-02-0116112010.1038/s41467-025-57295-7Kingdom-specific lipid unsaturation calibrates sequence evolution in membrane arm subunits of eukaryotic respiratory complexesPooja Gupta0Sristi Chakroborty1Arun K. Rathod2K. Ranjith Kumar3Shreya Bhat4Suparna Ghosh5Pallavi Rao T6Kameshwari Yele7Raman Bakthisaran8R. Nagaraj9Moutusi Manna10Swasti Raychaudhuri11CSIR- Centre for Cellular and Molecular Biology, Uppal RoadCSIR- Centre for Cellular and Molecular Biology, Uppal RoadAcademy of Scientific and Innovative Research (AcSIR)CSIR- Centre for Cellular and Molecular Biology, Uppal RoadCSIR- Centre for Cellular and Molecular Biology, Uppal RoadCSIR- Centre for Cellular and Molecular Biology, Uppal RoadCSIR- Centre for Cellular and Molecular Biology, Uppal RoadCSIR- Centre for Cellular and Molecular Biology, Uppal RoadCSIR- Centre for Cellular and Molecular Biology, Uppal RoadCSIR- Centre for Cellular and Molecular Biology, Uppal RoadAcademy of Scientific and Innovative Research (AcSIR)CSIR- Centre for Cellular and Molecular Biology, Uppal RoadAbstract 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.https://doi.org/10.1038/s41467-025-57295-7 |
| spellingShingle | Pooja Gupta Sristi Chakroborty Arun K. Rathod K. Ranjith Kumar Shreya Bhat Suparna Ghosh Pallavi Rao T Kameshwari Yele Raman Bakthisaran R. Nagaraj Moutusi Manna Swasti Raychaudhuri Kingdom-specific lipid unsaturation calibrates sequence evolution in membrane arm subunits of eukaryotic respiratory complexes Nature Communications |
| title | Kingdom-specific lipid unsaturation calibrates sequence evolution in membrane arm subunits of eukaryotic respiratory complexes |
| title_full | Kingdom-specific lipid unsaturation calibrates sequence evolution in membrane arm subunits of eukaryotic respiratory complexes |
| title_fullStr | Kingdom-specific lipid unsaturation calibrates sequence evolution in membrane arm subunits of eukaryotic respiratory complexes |
| title_full_unstemmed | Kingdom-specific lipid unsaturation calibrates sequence evolution in membrane arm subunits of eukaryotic respiratory complexes |
| title_short | Kingdom-specific lipid unsaturation calibrates sequence evolution in membrane arm subunits of eukaryotic respiratory complexes |
| title_sort | kingdom specific lipid unsaturation calibrates sequence evolution in membrane arm subunits of eukaryotic respiratory complexes |
| url | https://doi.org/10.1038/s41467-025-57295-7 |
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