biostudies-literatureCui GAmerican Heart AssociationBLRD VABSFNIDDK NIH HHSNHLBI NIH HHSIsmail Moustafa Scholar FundGreat Lakes Fishery CommissionVeterans Administration Merit ReviewNIHCF Foundation421-430.e3https://www.ebi.ac.uk/biostudies/studies/S-EPMC7665244biostudies-literatureUnknown51(4)The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel central to the development of secretory diarrhea and cystic fibrosis. The oldest CFTR ortholog identified is from dogfish shark, which retains similar structural and functional characteristics to the mammalian protein, thereby highlighting CFTR's critical role in regulating epithelial ion transport in vertebrates. However, the identification of an early CFTR ortholog with altered structure or function would provide critical insight into the evolution of epithelial anion transport. Here, we describe the earliest known CFTR, expressed in sea lamprey (Petromyzon marinus), with unique structural features, altered kinetics of activation and sensitivity to inhibition, and altered single-channel conductance compared to human CFTR. Our data provide the earliest evolutionary evidence of CFTR, offering insight regarding changes in gene and protein structure that underpin evolution from transporter to anion channel. Importantly, these data provide a unique platform to enhance our understanding of vertebrate phylogeny over a critical period of evolutionary expansion.Developmental cellAn Ancient CFTR Ortholog Informs Molecular Evolution in ABC Transporters.PMC766524420133911 I01 BX001756R01 DK05648116SDG27040000R01 HL102371SENDER13XX0HL1023715R01-DK056481-07MCCART17G0R35 HL135710I01 BX001756Gaggar ALi JHong JMcCarty NAImhoff BCottrill KChung-Davidson YWLi WSorscher ESenderowitz HInfield DBlalock JECui GKhazanov NXu XSimhaev LStauffer BfalseAn Ancient CFTR Ortholog Informs Molecular Evolution in ABC Transporters.The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel central to the development of secretory diarrhea and cystic fibrosis. The oldest CFTR ortholog identified is from dogfish shark, which retains similar structural and functional characteristics to the mammalian protein, thereby highlighting CFTR's critical role in regulating epithelial ion transport in vertebrates. However, the identification of an early CFTR ortholog with altered structure or function would provide critical insight into the evolution of epithelial anion transport. Here, we describe the earliest known CFTR, expressed in sea lamprey (Petromyzon marinus), with unique structural features, altered kinetics of activation and sensitivity to inhibition, and altered single-channel conductance compared to human CFTR. Our data provide the earliest evolutionary evidence of CFTR, offering insight regarding changes in gene and protein structure that underpin evolution from transporter to anion channel. Importantly, these data provide a unique platform to enhance our understanding of vertebrate phylogeny over a critical period of evolutionary expansion.2019-01-01T00:00:00Z2019 Nov2024-11-06T20:32:14.351Z2020-11-22T09:40:36ZS-EPMC76652443167985810.1016/j.devcel.2019.09.017