Membrane composition influences the topology bias of bacterial integral membrane proteins

Small multidrug resistance (SMR) protein family members confer bacterial resistance to toxic antiseptics and are believed to function as dual topology oligomers. If dual topology is essential for SMR activity, then the topology bias should change as bacterial membrane lipid compositions alter to maintain a “neutral” topology bias. To test this hypothesis, a bioinformatic analysis of bacterial SMR protein sequences was performed to determine a membrane protein topology based on charged amino acid residues within loops, and termini regions according to the positive inside rule. Three bacterial lipid membrane parameters were examined, providing the proportion of polar lipid head group charges at the membrane surface (PLH), the relative hydrophobic fatty acid length (FAL), and the proportion of fatty acid unsaturation (FAU). Our analysis indicates that individual SMR pairs, and to a lesser extent SMR singleton topology biases, are significantly correlated to increasing PLH, FAL and FAU differences validating the hypothesis. Correlations between the topology biases of SMR proteins identified in Gram + compared to Gram − species and each lipid parameter demonstrated a linear inverse relationship.

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► Mean SMR topology bias values differ between bacterial Gram + and Gram − phyla.
► Polar lipid head group charges (PLH) inversely correlate to SMR topology biases.
► SMR singleton topology biases show opposite correlations to PLH by Gram type.
► In addition to PLH, acyl chain length and unsaturation correlate with SMR topology.
► SMR topology biases using both +/− charged amino acids improve lipid correlations.