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J. Biol. Chem., Vol. 282, Issue 42, 30728-30736, October 19, 2007

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Interacting Proteins Dictate Function of the Minimal START Domain Phosphatidylcholine Transfer Protein/StarD2^*

Keishi Kanno¹, Michele K. Wu, Diana S. Agate, Brandon J. Fanelli, Neil Wagle^¶2, Erez F. Scapa³, Chinweike Ukomadu, and David E. Cohen^¶4

From the Department of Medicine, Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, the Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10467, and ^¶Division of Health and Sciences and Technology, Harvard-Massachusetts Institute of Technology, Boston, Massachusetts 02115

The Star (steroidogenic acute regulatory protein)-related transfer (START) domain superfamily is characterized by a distinctive lipid-binding motif. START domains typically reside in multidomain proteins, suggesting their function as lipid sensors that trigger biological activities. Phosphatidylcholine transfer protein (PC-TP, also known as StarD2) is an example of a START domain minimal protein that consists only of the lipid-binding motif. PC-TP, which binds phosphatidylcholine exclusively, is expressed during embryonic development and in several tissues of the adult mouse, including liver. Although it catalyzes the intermembrane exchange of phosphatidylcholines in vitro, this activity does not appear to explain the various metabolic alterations observed in mice lacking PC-TP. Here we demonstrate that PC-TP function may be mediated via interacting proteins. Yeast two-hybrid screening using libraries prepared from mouse liver and embryo identified Them2 (thioesterase superfamily member 2) and the homeodomain transcription factor Pax3 (paired box gene 3), respectively, as PC-TP-interacting proteins. These were notable because the START domain superfamily contains multidomain proteins in which the START domain coexists with thioesterase domains in mammals and with homeodomain transcription factors in plants. Interactions were verified in pulldown assays, and colocalization with PC-TP was confirmed within tissues and intracellularly. The acyl-CoA thioesterase activity of purified recombinant Them2 was markedly enhanced by recombinant PC-TP. In tissue culture, PC-TP coactivated the transcriptional activity of Pax3. These findings suggest that PC-TP functions as a phosphatidylcholine-sensing molecule that engages in diverse regulatory activities that depend upon the cellular expression of distinct interacting proteins.

Received for publication, May 7, 2007 , and in revised form, July 24, 2007.

^* This work was supported by National Institutes of Health Grants DK56626 and DK48873, an Established Investigator Award from the American Heart Association, and an International HDL Research Awards Program Grant (to D. E. C.). This work was also supported in part by Harvard Digestive Diseases Center Grant P30 DK34854. 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.

¹ Recipient of an Evelyn and James Silver Memorial Postdoctoral Research Fellowship Award from the American Liver Foundation.

² Recipient of a Howard Hughes Medical Institute Predoctoral Research Award.

³ Recipient of an American Liver Foundation Irwin M. Arias Postdoctoral Research Fellowship Award.

⁴ To whom correspondence should be addressed: Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115. Tel.: 617-525-7846; Fax: 617-264-6368; E-mail: dcohen{at}partners.org.

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