Article
- The EMBO Journal (2005) 24, 4124 - 4132
- doi:10.1038/sj.emboj.7600872
Published online: 10 November 2005
Subject Categories:
Metalloendoprotease cleavage triggers gelsolin amyloidogenesis
Lesley J Page1,3,a, Ji Young Suk2,4,a, Mary E Huff2,4, Hee-Jong Lim2,4, John Venable1, John Yates III1, Jeffery W Kelly2,4 and William E Balch1,3
- Departments of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA
- Institute for Childhood and Neglected Diseases, The Scripps Research Institute, La Jolla, CA, USA
- Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA
Correspondence to:
William E Balch, Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, MB6, La Jolla, CA 92037, USA. Tel.: + 1 858 784 2310; Fax: +1 858 784 9126; E-mail: webalch@scripps.edu
Jeffery W Kelly, Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, BCC506, La Jolla, CA 92037, USA. Tel.: +1 858 784 9880; Fax: +1 858 784 9899; E-mail: jkelly@scripps.edu
aThese authors contributed equally to this work
Received 23 May 2005; Accepted 20 October 2005
Abstract
Amyloid diseases like Alzheimer's disease and familial amyloidosis of Finnish type (FAF) stem from endoproteolytic cleavage of a precursor protein to generate amyloidogenic peptides that accumulate as amyloid deposits in a tissue-specific manner. FAF patients deposit both 8 and 5 kDa peptides derived from mutant (D187Y/N) plasma gelsolin in the extracellular matrix (ECM). The first of two aberrant sequential proteolytic events is executed by furin to yield a 68 kDa (C68) secreted fragment. We now identify the metalloprotease MT1-matrix metalloprotease (MMP), an integral membrane protein active in the ECM, as a protease that processes C68 to the amyloidogenic peptides. We further demonstrate that ECM components are capable of accelerating gelsolin amyloidogenesis. Proteolysis by MT1-MMP-like proteases proximal to the unique chemical environment of the ECM offers an explanation for the tissue-specific deposition observed in FAF and provides critical insight into new therapeutic strategies.
Keywords:
- amyloid,
- gelsolin,
- glycosaminoglycan,
- matrix metalloprotease,
- MT1-MMP
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