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J. Biol. Chem., Vol. 279, Issue 36, 37886-37894, September 3, 2004

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Internalization of Exogenously Added Memapsin 2 (-Secretase) Ectodomain by Cells Is Mediated by Amyloid Precursor Protein^*

Xiang-Ping Huang, Wan-Pin Chang, Gerald Koelsch, Robert T. Turner, III, Florea Lupu¶, and Jordan Tang||

From the Protein Studies Program and ^¶Cardiovascular Biology Program, Oklahoma Medical Research Foundation and Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center and Zapaq Inc., Oklahoma City, Oklahoma 73104

Memapsin 2 (-secretase) is the protease that initiates cleavage of amyloid precursor protein (APP) leading to the production of amyloid- (A) peptide and the onset of Alzheimer's disease. Both APP and memapsin 2 are Type I transmembrane proteins and are endocytosed into endosomes where APP is cleaved by memapsin 2. Separate endocytic signals are located in the cytosolic domains of these proteins. We demonstrate here that the addition of the ectodomain of memapsin 2 (M2_ED) to cells transfected with native APP or APP Swedish mutant (APPsw) resulted in the internalization of M2_ED into endosomes with increased A production. These effects were reduced by treatment with glycosylphosphatidylinositol-specific phospholipase C. The nontransfected parental cells had little internalization of M2_ED. The internalization of M2_ED was dependent on the endocytosis signal in APP, because the expression of a mutant APP that lacks its endocytosis signal failed to support M2_ED internalization. These results suggest that exogenously added M2_ED interacts with the ectodomain of APP on the cell surface leading to the internalization of M2_ED, supported by fluorescence resonance energy transfer experiments. The interactions between the two proteins is not due to the binding of substrate APPsw to the active site of memapsin 2, because neither a potent active site binding inhibitor of memapsin 2 nor an antibody directed to the -secretase site of APPsw had an effect on the uptake of M2_ED. In addition, full-length memapsin 2 and APP, immunoprecipitated together from cell lysates, suggested that the interaction of these two proteins is part of the native cellular processes.

Received for publication, February 26, 2004 , and in revised form, June 11, 2004.

^* This work was supported in part by National Institutes of Health Grant AG-18933 and by an Alzheimer's Association Pioneer Award (to J. T.). 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.

^|| Holder of the J. G. Puterbaugh Chair in Medical Research at the Oklahoma Medical Research Foundation. To whom correspondence should be addressed: Protein Studies Program, Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK 73104. Tel.: 405-271-7291; Fax: 405-271-7249; E-mail: jordan-tang{at}omrf.ouhsc.edu.

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