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J. Biol. Chem., Vol. 280, Issue 18, 17945-17952, May 6, 2005

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Functional Characterization of the MENTAL Domain^*

Fabien Alpy, Vinoth K. Latchumanan, Valérie Kedinger¶, Agnes Janoshazi, Christoph Thiele||, Corinne Wendling, Marie-Christine Rio, and Catherine Tomasetto**

From the Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Pathologie Moléculaire, UPR 6520 CNRS/U596 INSERM/Université Louis Pasteur, BP10142, 67404 Illkirch, C. U. de Strasbourg, France and ^||Max-Plank-Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany

Human metastatic lymph node (MLN) 64 is composed of two conserved regions. The amino terminus contains a conserved membrane-spanning MENTAL (MLN64 NH₂-terminal) domain shared with an unique protein called MENTHO (MLN64 NH₂-terminal domain homologue) and targets the protein to late endosome. The carboxyl-terminal domain is composed of a cholesterol binding steroidogenic acute regulatory-related lipid transfer domain exposed to the cytoplasm. MENTHO overexpression leads to the accumulation of enlarged endosomes. In this study, we show that MLN64 overexpression also induces the formation of enlarged endosomes, an effect that is probably mediated by the MENTAL domain. Using an in vivo photocholesterol binding assay, we find that the MENTAL domain of MLN64 is a cholesterol binding domain. Moreover, glutathione S-transferase pull-down or co-immunoprecipitation experiments demonstrate that this domain mediates homo- and hetero-interaction of MLN64 and MENTHO. In living cells, the expression of paired yellow fluorescent and cyan fluorescent fusion proteins show MENTHO homo-interaction and its interaction with MLN64. These data indicate that within late-endosomal membranes, MLN64 and MENTHO define discrete cholesterol-containing subdomains. The MENTAL domain might serve to maintain cholesterol at the membrane of late endosomes prior to its shuttle to cytoplasmic acceptor(s).

Received for publication, January 20, 2005 , and in revised form, February 17, 2005.

^* This work was supported by funds from the Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Université Louis Pasteur (ULP), and the Lique Nationale Contre le Cancer Comités du Haut-Rhin et du Bas-Rhin and from the Association pour la Recherche sur le Cancer (ARC). 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.

Recipient of an Association pour la Recherche sur le Cancer (ARC) fellowship.

^¶ Recipient of a Fondation pour la Recherche Medicale (FRM) fellowship.

^** To whom correspondence should be addressed: IGBMC, 1 rue Laurent Fries, BP 10142, 67404 Illkirch Cedex, France. Tel.: 33-3-88-65-35-19; Fax: 33-3-88-65-32-01; E-mail: cat{at}igbmc.u-strasbg.fr.

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