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J. Biol. Chem., Vol. 278, Issue 45, 44584-44592, November 7, 2003

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Xenopus Autosomal Recessive Hypercholesterolemia Protein Couples Lipoprotein Receptors with the AP-2 Complex in Oocytes and Embryos and Is Required for Vitellogenesis^*

Yi Zhou, Jian Zhang, and Mary Lou King¶

From the Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, Florida 33136 and the Center for Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China

ARH is required for normal endocytosis of the low density lipoprotein (LDL) receptor in liver and mutations within this gene cause autosomal recessive hypercholesterolemia in humans. xARH is a localized maternal RNA in Xenopus with an unknown function in oogenesis and embryogenesis. Like ARH, xARH contains a highly conserved phosphotyrosine binding domain and a clathrin box. To address the function of xARH, we examined its expression pattern in development and used pull-down experiments to assess interactions between xARH, lipoprotein receptors and proteins in embryo extracts. xARH was detected concentrated at the cell periphery as well as in the perinuclear region of oocytes and embryos. In pull-down experiments, the xARH phosphotyrosine binding domain interacted with the LDL and vitellogenin receptors found in Xenopus oocytes and embryos. Mutations within the receptor internalization signal specifically abolished this interaction. The xARH C-terminal region pulled-down several proteins from embryo extracts including - and -adaptins, subunits of the AP-2 endocytic complex. Mutations within either of the two D(F/W) motifs found in xARH abolished binding to - and -adaptins. Expression of a dominant negative mutant of xARH missing the clathrin box and one functional D(F/W) motif severely inhibited endocytosis of vitellogenin in cultured oocytes. The data indicate that xARH acts as an adaptor protein linking LDL and vitellogenin receptors directly with the AP-2 complex. In oocytes, we propose that xARH mediates the uptake of lipoproteins from the blood for storage in endosomes and later use in the embryo. Our findings point to an evolutionarily conserved function for ARH in lipoprotein uptake.

Received for publication, August 11, 2003

^* This work was supported by grants from the National Science Foundation (IBN 96-01209) and National Institutes of Health (GM33932) (to M. L. K.). 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. Tel.: 305-243-5643; Fax: 305-545-7166; E-mail: mking{at}med.miami.edu.

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