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Molecular and Cellular Biology, August 2006, p. 5921-5931, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.00315-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Understanding the Molecular Basis of the Interaction between NDPK-A and AMPK {alpha}1

Russell M. Crawford,1 Kate J. Treharne,1 Sandrine Arnaud-Dabernat,2 Jean-Yves Daniel,2 Marc Foretz,3 Benoit Viollet,3 and Anil Mehta1*

Department of Maternal and Child Health Sciences, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, United Kingdom,1 Laboratoire de Biologie de la Differenciation et du Developpement, Universite Victor Segalen Bordeaux 2, EA 3674, 33076 Bordeaux Cedex, France,2 INSERM U567, CNRS URM8104, Université Paris 5, Institut Cochin, Dpt. GDPM, 24 rue du Fg Saint Jacques, 75014 Paris, France3

Received 21 February 2006/ Returned for modification 28 March 2006/ Accepted 26 April 2006

Nucleoside diphosphate kinase (NDPK) (nm23/awd) belongs to a multifunctional family of highly conserved proteins (~16 to 20 kDa) including two well-characterized isoforms (NDPK-A and -B). NDPK catalyzes the conversion of nucleoside diphosphates to nucleoside triphosphates, regulates a diverse array of cellular events, and can act as a protein histidine kinase. AMP-activated protein kinase (AMPK) is a heterotrimeric protein complex that responds to the cellular energy status by switching off ATP-consuming pathways and switching on ATP-generating pathways when ATP is limiting. AMPK was first discovered as an activity that inhibited preparations of acetyl coenzyme A carboxylase 1 (ACC1), a regulator of cellular fatty acid synthesis. We recently reported that NDPK-A (but not NDPK-B) selectively regulates the {alpha}1 isoform of AMPK independently of the AMP concentration such that the manipulation of NDPK-A nucleotide trans-phosphorylation activity to generate ATP enhanced the activity of AMPK. This regulation occurred irrespective of the surrounding ATP concentration, suggesting that "substrate channeling" was occurring with the shielding of NDPK-generated ATP from the surrounding medium. We speculated that AMPK {alpha}1 phosphorylated NDPK-A during their interaction, and here, we identify two residues on NDPK-A targeted by AMPK {alpha}1 in vivo. We find that NDPK-A S122 and S144 are phosphorylated by AMPK {alpha}1 and that the phosphorylation status of S122, but not S144, determines whether substrate channeling can occur. We report the cellular effects of the S122 mutation on ACC1 phosphorylation and demonstrate that the presence of E124 (absent in NDPK-B) is necessary and sufficient to permit both AMPK {alpha}1 binding and substrate channeling.

* Corresponding author. Mailing address: Department of Maternal and Child Health Sciences, University of Dundee, Dundee DD1 9SY, United Kingdom. Phone: 44 (0)1382 660111, ext. 32555. Fax: 44 (0)1382 632597. E-mail: a.mehta{at}dundee.ac.uk.

Molecular and Cellular Biology, August 2006, p. 5921-5931, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.00315-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Treharne, K. J., Crawford, R. M., Xu, Z., Chen, J.-H., Best, O. G., Schulte, E. A., Gruenert, D. C., Wilson, S. M., Sheppard, D. N., Kunzelmann, K., Mehta, A. (2007). Protein Kinase CK2, Cystic Fibrosis Transmembrane Conductance Regulator, and the {Delta}F508 Mutation: F508 DELETION DISRUPTS A KINASE-BINDING SITE. J. Biol. Chem. 282: 10804-10813 [Abstract] [Full Text]  


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