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J. Biol. Chem., Vol. 278, Issue 32, 29979-29986, August 8, 2003

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Specific Binding of Dehydroepiandrosterone to the N Terminus of the Microtubule-associated Protein MAP2^*

Emmanuelle Laurine  , Daniel Lafitte ¶, Catherine Grégoire  ||, Eric Sérée ¶, Erwann Loret ¶, Soazig Douillard ¶, Bernard Michel **, Claudette Briand ¶ and Jean-Michel Verdier  

From the École Pratique des Hautes Études, Université Montpellier II, Place Eugène Bataillon, CC94, 34095 Montpellier cedex 05, France, ^¶UMR CNRS 6032, Faculté de Pharmacie, 13385 Marseille cedex 05, France, and ^**Unité de Neurogériatrie, Hôpital Sainte-Marguerite, 13385 Marseille cedex 05, France

The effect of neurosteroids is mediated through their membrane or nuclear receptors. However, no dehydroepiandrosterone (DHEA)-specific receptors have been evidenced so far in the brain. In this paper, we showed by isothermal titration calorimetry that the DHEA specifically binds to the dendritic brain microtubule-associated protein MAP2C with an association constant of 2.7 x 10⁷ M^–1 and at a molar ratio of 1:1. By partial tryptic digestions and mass spectrometry analysis, we found that the binding involved the N-terminal region of MAP2C. Interestingly, MAP2C displays homologies with 17-hydroxysteroid dehydrogenase 1, an enzyme required for estrogen synthesis. Based on these sequence homologies and on the x-ray structure of the DHEA-binding pocket of 17-hydroxysteroid dehydrogenase 1, we modeled the complex of DHEA with MAP2C. The binding of DHEA to MAP2C involved specific hydrogen bonds that orient the steroid into the pocket. This work suggests that DHEA can directly influence brain plasticity via MAP2C binding. It opens interesting ways for understanding the role of DHEA in the brain.

Received for publication, March 28, 2003 , and in revised form, May 12, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by the Groupe de Recherche sur la Maladie d'Alzheimer and France Alzheimer.

^|| Supported by Groupement d'Intéret Scientifique "Infections à prions" Grant A43.

To whom all correspondence should be addressed. Tel./Fax: 33-4-67-14-32-91; E-mail: verdier{at}univ-montp2.fr.

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This article has been cited by other articles:

				V. Fontaine-Lenoir, B. Chambraud, A. Fellous, S. David, Y. Duchossoy, E.-E. Baulieu, and P. Robel Microtubule-associated protein 2 (MAP2) is a neurosteroid receptor PNAS, March 21, 2006; 103(12): 4711 - 4716. [Abstract] [Full Text] [PDF]