Metalloprotease Meprin β Generates Nontoxic N-terminal Amyloid Precursor Protein Fragments in Vivo
Metalloprotease Meprin β Generates Nontoxic N-terminal Amyloid Precursor Protein Fragments in Vivo
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DOI：
10.1074/jbc.m111.252718
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发表时间：
2011-08-05
影响因子：
4.8
通讯作者：
Becker-Pauly, Christoph
中科院分区：
文献类型：
--
作者：
Jefferson, Tamara;Causevic, Mirsada;Becker-Pauly, Christoph
Identification of physiologically relevant substrates is still the most challenging part in protease research for understanding the biological activity of these enzymes. The zinc-dependent metalloprotease meprin beta is known to be expressed in many tissues with functions in health and disease. Here, we demonstrate unique interactions between meprin beta and the amyloid precursor protein (APP). Although APP is intensively studied as a ubiquitously expressed cell surface protein, which is involved in Alzheimer disease, its precise physiological role and relevance remain elusive. Based on a novel proteomics technique termed terminal amine isotopic labeling of substrates (TAILS), APP was identified as a substrate for meprin beta. Processing of APP by meprin beta was subsequently validated using in vitro and in vivo approaches. N-terminal APP fragments of about 11 and 20 kDa were found in human and mouse brain lysates but not in meprin beta(-/-)mouse brain lysates. Although these APP fragments were in the range of those responsible for caspase-induced neurodegeneration, we did not detect cytotoxicity to primary neurons treated by these fragments. Our data demonstrate that meprin beta is a physiologically relevant enzyme in APP processing.
