Information de reference pour ce titreAccession Number: | 00006056-199912020-00028.
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Author: | Sinha, Sukanto; Anderson, John P.; Barbour, Robin; Basi, Guriqbal S.; Caccavello, Russell; Davis, David; Doan, Minhtam; Dovey, Harry F.; Frigon, Normand; Hong, Jin; Jacobson-Croak, Kirsten; Jewett, Nancy; Keim, Pamela; Knops, Jeroen; Lieberburg, Ivan; Power, Michael; Tan, Hua; Tatsuno, Gwen; Tung, Jay; Schenk, Dale; Seubert, Peter; Suomensaari, Susanna M.; Wang, Shuwen; Walker, Donald; Zhao, Jun; McConlogue, Lisa; John, Varghese
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Institution: | Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, California 94080, USA
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Title: | Purification and cloning of amyloid precursor protein [beta]-secretase from human brain.[Letter]
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Source: | Nature. 402(6761):537-540, December 2, 1999.
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Abstract: | Proteolytic processing of the amyloid precursor protein (APP) generates amyloid [beta] (A[beta]) peptide, which is thought to be causal for the pathology and subsequent cognitive decline in Alzheimer's disease. Cleavage by [beta]-secretase at the amino terminus of the A[beta] peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of [beta]-cleaved soluble APP 1, and a corresponding cell-associated carboxy-terminal fragment. Cleavage of the C-terminal fragment by [gamma]-secretase(s) leads to the formation of A[beta]. The pathogenic mutation K670M671 -> N670L671 at the [beta]-secretase cleavage site in APP 2, which was discovered in a Swedish family with familial Alzheimer's disease, leads to increased [beta]-secretase cleavage of the mutant substrate 3. Here we describe a membrane-bound enzyme activity that cleaves full-length APP at the [beta]-secretase cleavage site, and find it to be the predominant [beta]-cleavage activity in human brain. We have purified this enzyme activity to homogeneity from human brain using a new substrate analogue inhibitor of the enzyme activity, and show that the purified enzyme has all the properties predicted for [beta]-secretase. Cloning and expression of the enzyme reveals that human brain [beta]-secretase is a new membrane-bound aspartic proteinase.
©: 1999 Macmillian Magazines Ltd
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Language: | English.
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Document Type: | Letters To Nature.
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Journal Subset: | Life Sciences. Physical Science & Engineering.
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ISSN: | 0028-0836
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NLM Journal Code: | 0410462, nsc
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