Fluhrer Regina, Capell Anja, Westmeyer Gil, Willem Michael, Hartung Bianka, Condron Margaret M, Teplow David B, Haass Christian, Walter Jochen
Adolf Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Ludwig-Maximilians-University, Munich, Germany.
J Neurochem. 2002 Jun;81(5):1011-20. doi: 10.1046/j.1471-4159.2002.00908.x.
beta-Site amyloid precursor protein cleavage enzyme (BACE)-1 and BACE-2 are members of a novel family of membrane-bound aspartyl proteases. While BACE-1 is known to cleave beta-amyloid precursor protein (betaAPP) at the beta-secretase site and to be required for the generation of amyloid beta-peptide (Abeta), the role of its homologue BACE-2 in amyloidogenesis is less clear. We now demonstrate that BACE-1 and BACE-2 have distinct specificities in cleavage of betaAPP in cultured cells. Radiosequencing of the membrane-bound C-terminal cleavage product revealed that BACE-2 cleaves betaAPP in the middle of the Abeta domain between phenylalanines 19 and 20, resulting in increased secretion of APPs-alpha- and p3-like products and reduced production of Abeta species. This cleavage can occur in the Golgi and later secretory compartments. We also demonstrate that BACE-1-mediated cleavage of betaAPP at Asp1 of the Abeta domain can occur as early as in the endoplasmic reticulum, while cleavage at Glu11 occurs in later compartments. These data indicate that the distinct specificities of BACE-1 and BACE-2 in their cleavage of betaAPP differentially affect the generation of Abeta.
β位点淀粉样前体蛋白裂解酶（BACE）-1和BACE-2是膜结合天冬氨酸蛋白酶新家族的成员。虽然已知BACE-1在β-分泌酶位点裂解β淀粉样前体蛋白（βAPP），并且是淀粉样β肽（Aβ）生成所必需的，但其同源物BACE-2在淀粉样蛋白生成中的作用尚不清楚。我们现在证明，BACE-1和BACE-2在培养细胞中裂解βAPP具有不同的特异性。对膜结合的C末端裂解产物进行放射性测序显示，BACE-2在Aβ结构域中苯丙氨酸19和20之间裂解βAPP，导致APPs-α和p3样产物的分泌增加，Aβ种类的产生减少。这种裂解可发生在高尔基体和随后的分泌小室中。我们还证明，BACE-1介导的βAPP在Aβ结构域Asp1处的裂解最早可在内质网中发生，而在Glu11处的裂解发生在随后的小室中。这些数据表明，BACE-1和BACE-2在裂解βAPP方面的不同特异性对Aβ的产生有不同影响。
