Cleavage of amyloid-β precursor protein (APP) by membrane-type matrix metalloproteinases
Cleavage of amyloid-β precursor protein (APP) by membrane-type matrix metalloproteinases
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DOI：
10.1093/jb/mvj054
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发表时间：
2006-03-01
影响因子：
2.7
通讯作者：
Sato, H
中科院分区：
文献类型：
--
作者：
Ahmad, M;Takino, T;Sato, H
淀粉样蛋白-β 前体蛋白 (APP) 在从人胎盘 cDNA 文库中表达克隆时被鉴定为调节膜型基质金属蛋白酶-1 (MT1-MMP) 活性的基因产物。当与 APP 衔接蛋白 Fe65 共表达时，MT1-MMP 与 APP 在 HEK293T 细胞中的共表达诱导 APP 胞外域的裂解和脱落。在测试的MT-MMP中，MT3-MMP和MT5-MMP也导致了有效的APP脱落。重组 APP 蛋白在体外被 MT3-MMP 在 A(463) -M-464、N-579 -M-580、H-622-S-623 和 H-685 -Q(686) 肽键处裂解，其中包括淀粉样蛋白 P 肽区域内已知可产生 C 末端片段的裂解位点。 APP 的瑞典型突变体产生高水平的淀粉样 0 肽，在存在和不存在 Fe65 的情况下，MT3-MMP 比野生型 APP 更有效地切割 APP；然而，淀粉样蛋白 P 肽的产生不受 MT3-MMP 表达的影响。 MT3-MMP 的表达通过融合到 Gal4 DNA 结合和反式激活结构域的 APP 增强了 Fe65 依赖性反式激活。这些结果表明MT1-MMP、MT3-MMP和MT5-MMP在包括中枢神经系统在内的组织中APP功能的调节中发挥重要作用。
Amyloid-beta precursor protein (APP) was identified on expression cloning from a human placenta cDNA library as a gene product that modulates the activity of membrane-type matrix metalloproteinase-1 (MT1-MMP). Co-expression of MT1-MMP with APP in HEK293T cells induced cleavage and shedding of the APP ectodomain when co-expressed with APP adaptor protein Fe65. Among the MT-MMPs tested, MT3-MMP and MT5-MMP also caused efficient APP shedding. The recombinant APP protein was cleaved by MT3-MMP in vitro at the A(463) -M-464, N-579 -M-580, H-622-S-623, and H-685 -Q(686) peptide bonds, which included a cleavage site within the amyloid P peptide region known to produce a C-terminal fragment. The Swedish-type mutant of APP, which produces a high level of amyloid 0 peptide, was more effectively cleaved by MT3-MMP than wild-type APP in both the presence and absence of Fe65; however, amyloid P peptide production was not affected by MT3-MMP expression. Expression of MT3-MMP enhanced Fe65-dependent transactivation by APP fused to the Gal4 DNA-binding and transactivation domains. These results suggest that MT1-MMP, MT3-MMP and MT5-MMP should play an important role in the regulation of APP functions in tissues including the central nervous system.