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首页> 外文期刊>Biochemistry >Glu11 site cleavage and N-terminally truncated A beta production upon BACE overexpression.
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Glu11 site cleavage and N-terminally truncated A beta production upon BACE overexpression.

机译：BACE过表达时，Glu11位点切割和N末端截短的A beta产生。

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摘要

Amyloid beta peptides (A beta) are generated by the proteolytic processing of the amyloid beta precursor protein (APP). The newly identified beta-site APP-cleaving enzyme (BACE) cleaves APP at Asp1 as well as between Tyr10 and Glu11 of A beta, producing C-terminal fragments (CTFs) C99 and C89, respectively. Subsequent cleavage by gamma-secretase gives rise to A beta 1-40/42 and A beta 11-40/42. Although both full-length and A beta peptides truncated at residue 11 have been identified in amyloid plaques in the AD brain, the relative proportion of these two cleavage products produced by BACE and secreted into the medium by cultured cells is unknown. Using cell lines stably overexpressing BACE, we found that A beta 11-40 and A beta 11-42 are major A beta cleavage products generated by BACE. We further showed that BACE utilizes both full-length APP as well as C99 as substrates for the production of C89, and that A beta 11-40/42 can be generated by sequential cleavage of single APP molecules by BACE and gamma-secretase. Taken together, the abundance of A beta 11-40/42 produced by BACE suggests that their roles in AD pathogenesis may be underestimated.
机译：淀粉样蛋白β肽（A beta）是通过淀粉样蛋白β前体蛋白（APP）的蛋白水解过程产生的。新近鉴定的β位APP裂解酶（BACE）在Asp1以及Aβ的Tyr10和Glu11之间裂解APP，分别产生C端片段（CTF）C99和C89。随后被γ-分泌酶切割产生A beta 1-40 / 42和A beta 11-40 / 42。尽管在AD脑的淀粉样蛋白斑中已经鉴定出在残基11处截短的全长和Aβ肽，但是由BACE产生并由培养细胞分泌到培养基中的这两种裂解产物的相对比例是未知的。使用稳定地过表达BACE的细胞系，我们发现A beta 11-40和A beta 11-42是BACE产生的主要A beta裂解产物。我们进一步表明，BACE利用全长APP和C99作为底物来生产C89，并且可以通过BACE和伽马分泌酶顺序切割单个APP分子来生成A beta 11-40 / 42。综上所述，BACE产生的丰富的A beta 11-40 / 42表明它们在AD发病机理中的作用可能被低估了。

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