An intrinsic adenylate kinase activity regulates gating of the ABC transporter CFTR.
Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel in the ATP binding cassette (ABC) transporter family. Like other ABC transporters, it can hydrolyze ATP. Yet while ATP hydrolysis influences channel gating, it has long seemed puzzling that CFTR would require this reaction because anions flow passively through CFTR. Moreover, no other ion channel is known to require the large energy of ATP hydrolysis to gate. We found that CFTR also has adenylate kinase activity (ATP + AMP <=> ADP + ADP) that regulates gating. When functioning as an adenylate kinase, CFTR showed positive cooperativity for ATP suggesting its two nucleotide binding domains may dimerize. Thus, channel activity could be regulated by two different enzymatic reactions, ATPase and adenylate kinase, that share a common ATP binding site in the second nucleotide binding domain. At physiologic nucleotide concentrations, adenylate kinase activity, rather than ATPase activity may control gating, and therefore involve little energy consumption.
Randak
Christoph
C
Howard Hughes Medical Institute, Department of Internal Medicine and Physiology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Welsh
Michael J
MJ
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000263:Adenylate Kinase / Q000378:metabolism*; D001665:Binding Sites / Q000502:physiology; D002462:Cell Membrane / Q000201:enzymology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D019281:Dimerization; D004734:Energy Metabolism / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D009154:Mutation / Q000502:physiology; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology
D018528:ATP-Binding Cassette Transporters; C505032:CFTR protein, human; D010455:Peptides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D000263:Adenylate Kinase; D000251:Adenosine Triphosphatases