The Metalloprotease Meprin β Is an Alternative β-Secretase of APP.
The Metalloprotease Meprin β Is an Alternative β-Secretase of APP.
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DOI：
10.3389/fnmol.2016.00159
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发表时间：
2016
影响因子：
4.8
通讯作者：
Pietrzik CU
中科院分区：
文献类型：
--
作者：
Becker-Pauly C;Pietrzik CU
膜结合金属蛋白酶美普林β对结缔组织形成中的胶原纤维组装以及肠道黏液层的脱离以实现正常屏障功能非常重要。最近的蛋白质组学研究揭示了美普林β的数十种可能的新底物，包括淀粉样前体蛋白（APP）。研究表明，APP可被美普林β以不同方式切割，要么在β - 分泌酶位点切割，导致Aβ肽水平升高，要么在N - 末端切割，释放出11 kDa和20 kDa的肽片段。后一种情况被认为具有神经保护作用，而美普林β对APP胞外域的切割类似于BACE - 1，这与阿尔茨海默病的淀粉样蛋白假说相符，会促进神经退行性变。11 kDa和20 kDa的N - 末端肽片段是生理切割产物，因为在不同患病或非患病状态的人脑中都能发现它们，而在美普林β基因敲除动物的大脑中完全没有这些片段。美普林β不仅是APP等黏附分子的脱落酶，还被证明可在ADAM10的前结构域内进行切割。被激活的ADAM10（APP的α - 分泌酶）能够使美普林β从细胞表面脱落，从而消除β - 分泌酶活性。总之，美普林β似乎是APP加工过程中的一个新参与者，甚至会影响其他参与APP切割的酶。
The membrane bound metalloprotease meprin β is important for collagen fibril assembly in connective tissue formation and for the detachment of the intestinal mucus layer for proper barrier function. Recent proteomic studies revealed dozens of putative new substrates of meprin β, including the amyloid precursor protein (APP). It was shown that APP is cleaved by meprin β in distinct ways, either at the β-secretase site resulting in increased levels of Aβ peptides, or at the N-terminus releasing 11 kDa, and 20 kDa peptide fragments. The latter event was discussed to be rather neuroprotective, whereas the ectodomain shedding of APP by meprin β reminiscent to BACE-1 is in line with the amyloid hypothesis of Alzheimer's disease, promoting neurodegeneration. The N-terminal 11 kDa and 20 kDa peptide fragments represent physiological cleavage products, since they are found in human brains under different diseased or non-diseased states, whereas these fragments are completely missing in brains of meprin β knock-out animals. Meprin β is not only a sheddase of adhesion molecules, such as APP, but was additionally demonstrated to cleave within the prodomain of ADAM10. Activated ADAM10, the α-secretase of APP, is then able to shed meprin β from the cell surface thereby abolishing the β-secretase activity. All together meprin β seems to be a novel player in APP processing events, even influencing other enzymes involved in APP cleavage.
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