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

FEBS Letters

Tang, Jordan¹  He, Xiangyuan¹  Chang, Wan-Pin¹  Koelsch, Gerald¹ 

[1] Protein Studies Program, Oklahoma Medical Research Foundation, 825 N.E. 13 Street, Oklahoma City, OK 73104, USA

关键词: Alzheimer's disease;    Memapsin 2;    β-Secretase;    Endocytosis;    GGA1;    GGA2;    APP;    β-amyloid precursor protein;    Aβ;    β-amyloid peptide;    GST;    glutathione S-transferase;    CI-MPR;    cation-independent mannose-6-phosphate receptor;    CD-MPR;    cation-dependent mannose-6-phosphate receptor;   

DOI  :  10.1016/S0014-5793(02)03052-1

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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 Asp⁴⁹⁶, Leu⁴⁹⁹ and Leu⁵⁰⁰ 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.

【 授权许可】

Unknown