Broad phylogenetic analysis of cation/proton antiporters reveals transport determinants

• DOI: 10.1038/s41467-018-06770-5
• Publication Date: 2018-10-05T10:01:43Z
• Authors: Gal Masrati; Manish Dwivedi; Abraham Rimon; Yael Gluck-Margolin; Amit Kessel; Haim Ashkenazy; Itay Mayrose; Etana Padan; Nir Ben-Tal
• Keywords: Models, Molecular; 0301 basic medicine; 0303 health sciences; Binding Sites; Valinomycin; Science; Q; Sodium; Article; Antiporters; Protein Transport; 03 medical and health sciences; Cations; Mutation; Humans; Amino Acids; Protons; Phylogeny

AbstractCation/proton antiporters (CPAs) play a major role in maintaining living cells’ homeostasis. CPAs are commonly divided into two main groups, CPA1 and CPA2, and are further characterized by two main phenotypes: ion selectivity and electrogenicity. However, tracing the evolutionary relationships of these transporters is challenging because of the high diversity within CPAs. Here, we conduct comprehensive evolutionary analysis of 6537 representative CPAs, describing the full complexity of their phylogeny, and revealing a sequence motif that appears to determine central phenotypic characteristics. In contrast to previous suggestions, we show that the CPA1/CPA2 division only partially correlates with electrogenicity. Our analysis further indicates two acidic residues in the binding site that carry the protons in electrogenic CPAs, and a polar residue in the unwound transmembrane helix 4 that determines ion selectivity. A rationally designed triple mutant successfully converted the electrogenic CPA, EcNhaA, to be electroneutral.