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J. Biol. Chem., Vol. 279, Issue 52, 54770-54782, December 24, 2004

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Human Nischarin/Imidazoline Receptor Antisera-selected Protein Is Targeted to the Endosomes by a Combined Action of a PX Domain and a Coiled-coil Region^*

Koh-Pang Lim and Wanjin Hong, A faculty member of the Dept. of Biochemistry, National University of Singapore

From the Membrane Biology Laboratory, Institute of Molecular and Cell Biology, Proteos Building, 61 Biopolis Drive, Singapore 138673, Singapore

Around 50 mammalian and 15 yeast proteins are known to contain the phox (PX) domain, the majority (about 30) of which is classified as sorting nexins (SNXs). The PX domain, a hallmark of these proteins, is a conserved stretch of about 120 amino acids and is recently shown to mediate phosphoinositide binding. A few PX domain proteins (including some SNXs) have been shown to participate in diverse cellular processes such as protein sorting, signal transduction, and vesicle fusion. In this report, we present our results supporting a role of human IRAS to act as a SNX. The mouse homologue, previously identified as Nischarin, has been shown to interact with the ₅ subunit of integrin and inhibit cell migration (Alahari, S. K., Lee J. W., and Juliano R. L. (2000) J. Cell Biol. 51, 1141-1154). Its human homologue (imidazoline receptor antisera-selected (IRAS)), on the other hand, contains an NH₂-terminal extension and is a larger protein of 1504 amino acids consisting of an NH₂-terminal PX domain, 5 putative leucine-rich repeats, a predicted coiled-coil domain, and a long COOH-terminal region. We show that it has the ability to homo-oligomerize via its coiled-coil region. The PX domain of IRAS is essential for association with phosphatidylinositol 3-phosphate-enriched endosomal membranes. However, the PX domain of IRAS alone is insufficient for its localization to endosomes, unless the coiled-coil domain was included or it is artificially dimerized by glutathione S-transferase. Interaction of human IRAS with ₅ integrin is not affected by the NH₂-terminal extension, and overexpression of IRAS could cause a redistribution of surface ₅ integrin to intracellular endosomal structures.

Received for publication, October 4, 2004

^* This work was funded in part by Agency for Science, Technology and Research (A^*STAR) (to W. H.). 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.

To whom correspondence should be addressed: Membrane Biology Lab., Institute of Molecular and Cell Biology, Proteos Bldg. (Rm. 5-21B), 61 Biopolis Dr., Singapore 138673, Singapore. Tel.: 65-6586-9606; Fax: 65-6779-1117; E-mail: mcbhwj{at}imcb.a-star.edu.sg.

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