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bioRxiv · 10.1101/2024.07.01.601479

Kingdom-specific lipid unsaturation shapes up sequence evolution in membrane arm subunits of eukaryotic respiratory complexes

Gupta, P.·Chakroborty, S.·Rathod, A. K.·Bhat, S.·Ghosh, S.·Rao T., P.·Nagaraj, R.·Manna, M.·Raychaudhuri, S.
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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 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 lipid-rich inner-mitochondrial membrane (IMM) and 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.

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Gupta, P., Chakroborty, S., Rathod, A. K., Bhat, S., Ghosh, S., Rao T., P., Nagaraj, R., Manna, M., Raychaudhuri, S.. 2024-07-03. Kingdom-specific lipid unsaturation shapes up sequence evolution in membrane arm subunits of eukaryotic respiratory complexes. https://doi.org/10.1101/2024.07.01.601479

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