ADP inhibits function of the ABC transporter cystic fibrosis transmembrane conductance regulator via its adenylate kinase activity

Christoph O Randak; Michael J Welsh

doi:10.1073/pnas.0409787102

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ADP inhibits function of the ABC transporter cystic fibrosis transmembrane conductance regulator via its adenylate kinase activity

Journal article

Open access

Peer reviewed

ADP inhibits function of the ABC transporter cystic fibrosis transmembrane conductance regulator via its adenylate kinase activity

Christoph O Randak and Michael J Welsh

Proceedings of the National Academy of Sciences - PNAS, Vol.102(6), pp.2216-2220

02/08/2005

DOI: 10.1073/pnas.0409787102

PMCID: PMC548590

PMID: 15684079

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Abstract

ADP interacts with the nucleotide-binding domains (NBDs) of the cystic fibrosis transmembrane conductance regulator (CFTR) to inhibit its Cl - channel activity. Because CFTR NBD2 has reversible adenylate kinase activity (ATP + AMP ⇆ ADP + ADP) that gates the channel, we asked whether ADP might inhibit current through this enzymatic activity. In adenylate kinases, binding of the two ADP molecules is cooperative. Consistent with this hypothesis, CFTR current inhibition showed positive cooperativity for ADP. We also found that ADP inhibition of current was attenuated when we prevented adenylate kinase activity with P 1 ,P 5 -di(adenosine-5′) pentaphosphate. Additional studies suggested that adenylate kinase-dependent inhibition involved phosphotransfer between two nucleotide diphosphates. These data indicate that the adenylate kinase reaction at NBD2 contributed to the inhibitory effect of ADP. Finding that ADP inhibits function via an adenylate kinase activity also helps explain the earlier observation that mutations that disrupt adenylate kinase activity also disrupt ADP inhibition. Thus, the results reveal a previously unrecognized mechanism by which ADP inhibits an ABC transporter.

phosphotransfer

Biological Sciences

chloride channel

ATPase

nucleotide-binding domain

Details

Title: Subtitle: ADP inhibits function of the ABC transporter cystic fibrosis transmembrane conductance regulator via its adenylate kinase activity
Creators: Christoph O Randak - Departments of Internal Medicine and Physiology and Biophysics, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Michael J Welsh - Departments of Internal Medicine and Physiology and Biophysics, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.102(6), pp.2216-2220
DOI: 10.1073/pnas.0409787102
PMID: 15684079
PMCID: PMC548590
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Language: English
Date published: 02/08/2005
Academic Unit: Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Pulmonary Medicine; Stead Family Department of Pediatrics; Neurosurgery; Internal Medicine
Record Identifier: 9984020641302771

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