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Molecular and Cellular Biology, November 2003, p. 8008-8018, Vol. 23, No. 22
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.22.8008-8018.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Phosphorylation-Elicited Quaternary Changes of GA Binding Protein in Transcriptional Activation

Morten Sunesen,1 Monique Huchet-Dymanus,1 Morten O. Christensen,2 and Jean-Pierre Changeux1*

Laboratoire Récepteurs et Cognition, CNRS URA 2182, Institut Pasteur, 75724 Paris Cedex 15, France,1 Institute of Clinical Chemistry and Laboratory Diagnostics, Heinrich Heine University Medical School, D-40225 Duesseldorf, Germany2

Received 17 March 2003/ Returned for modification 15 April 2003/ Accepted 6 August 2003

Enrichment of nicotinic acetylcholine receptors (nAChR) on the tip of the subjunctional folds of the postsynaptic membrane is a central event in the development of the vertebrate neuromuscular junction. This is attained, in part, through a selective transcription in the subsynaptic nuclei, and it has recently been shown that the GA binding protein (GABP) plays an important role in this compartmentalized expression. The neural factor heregulin (HRG) activates nAChR transcription in cultured cells by stimulating a signaling cascade of protein kinases. Hence, it is speculated that GABP becomes activated by phosphorylation, but the mechanism has remained elusive. To fully understand the consequences of GABP phosphorylation, we examined the effect of heregulin-elicited GABP phosphorylation on cellular localization, DNA binding, transcription, and mobility. We demonstrate that HRG-elicited phosphorylation dramatically changes the transcriptional activity and mobility of GABP. While phosphorylation of GABPß seems to be dispensable for these changes, phosphorylation of GABP{alpha} is crucial. Using fluorescence resonance energy transfer, we furthermore showed that phosphorylation of threonine 280 in GABP{alpha} triggers reorganizations of the quaternary structure of GABP. Taken together, these results support a model in which phosphorylation-elicited structural changes of GABP enable engagement in certain interactions leading to transcriptional activation.

* Corresponding author. Mailing address: Laboratoire Récepteurs et Cognition, CNRS URA 2182, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris cedex 15, France. Phone: 33 1 4568 8805. Fax: 33 1 4568 8836. E-mail: Changeux{at}pasteur.fr.

Molecular and Cellular Biology, November 2003, p. 8008-8018, Vol. 23, No. 22
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.22.8008-8018.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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