Memapsin 2 (β-secretase) cytosolic domain binds to the VHS domains of GGA1 and GGA2: implications on the endocytosis mechanism of memapsin 2

• Published in: FEBS letters 2002-07, Vol.524 (1), p.183-187
• Main Authors: He, Xiangyuan, Chang, Wan-Pin, Koelsch, Gerald, Tang, Jordan
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Vesicular Transport; ADP-Ribosylation Factors - chemistry; ADP-Ribosylation Factors - metabolism; Alzheimer's disease; Amino Acid Sequence; Amyloid Precursor Protein Secretases; APP, β-amyloid precursor protein; Aspartic Acid Endopeptidases - chemistry; Aspartic Acid Endopeptidases - metabolism; Aβ, β-amyloid peptide; Binding Sites; Carrier Proteins - chemistry; Carrier Proteins - metabolism; CD-MPR, cation-dependent mannose-6-phosphate receptor; CI-MPR, cation-independent mannose-6-phosphate receptor; Cloning, Molecular; Cytosol - metabolism; DNA, Complementary; Endocytosis; Endopeptidases; GGA1; GGA2; GST, glutathione S-transferase; Humans; Memapsin 2; Molecular Sequence Data; Proteins - chemistry; Proteins - metabolism; Sequence Homology, Amino Acid; β-Secretase
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/S0014-5793(02)03052-1

Memapsin 2, or β-secretase, is a membrane-anchored aspartic protease that initiates the cleavage of β-amyloid precursor protein (APP) leading to the production of β-amyloid peptide in the brain and the onset of Alzheimer’s disease. Memapsin 2 and APP are both endocytosed into endosomes for cleavage. Here we show that the cytosolic domain of memapsin 2, but not that of memapsin 1, binds the VHS domains of GGA1 and GGA2. Gel-immobilized VHS domains of GGA1 and GGA2 also bound to full-length memapsin 2 from cell mammalian lysates. Mutagenesis studies established that Asp 496, Leu 499 and Leu 500 were essential for the binding. The spacing of these three residues in memapsin 2 is identical to those in the cytosolic domains of mannose-6-phosphate receptors, sortilin and low density lipoprotein receptor-related protein 3. These observations suggest that the endocytosis and intracellular transport of memapsin 2, mediated by its cytosolic domain, may involve the binding of GGA1 and GGA2.