Nucleoside triphosphate pentose ring impact on CFTR gating and hydrolysis.
Alterations in the pentose ring of ATP have a major impact on cystic fibrosis transmembrane conductance regulator (CFTR) function. Both 2'- and 3'-deoxy-ATP (dATP) accelerate ion channel openings and stabilize open channel structure better than ATP. Purified wild-type CFTR hydrolyzes dATP. The apparent first-order rate constants for hydrolysis at low substrate concentration are the same for dATP and ATP. This suggests that product release and/or relaxation of the enzyme structure to the initial ligand free state is the rate-limiting step in the CFTR hydrolytic cycle. Circumvention of the normal requirement for protein kinase A phosphorylation of the R-domain for channel activation implies that the impact of the deoxyribonucleotide interaction with the nucleotide binding domains is transmitted to the channel-forming elements of the protein more readily than that of the ribonucleotide.
Aleksandrov
Andrei A
AA
Mayo Foundation and Mayo Clinic Scottsdale, S.C. Johnson Medical Research Center, 13400 E. Shea Blvd., Scottsdale, AZ 85259, USA. aleksand@mayo.edu
Aleksandrov
Luba
L
Riordan
John R
JR
D000255:Adenosine Triphosphate / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D003838:Deoxyadenine Nucleotides / Q000378:metabolism / Q000494:pharmacology; D004553:Electric Conductivity; D006868:Hydrolysis; D015640:Ion Channel Gating; D007700:Kinetics; D010766:Phosphorylation; D012266:Ribose / Q000737:chemistry
D003838:Deoxyadenine Nucleotides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D012266:Ribose; D000255:Adenosine Triphosphate; C026600:2'-deoxyadenosine triphosphate