Metalloendoprotease cleavage triggers gelsolin amyloidogenesis.
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.
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Lesley J
LJ
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Suk
Ji Young
JY
Huff
Mary E
ME
Lim
Hee-Jong
HJ
Venable
John
J
Yates
John
J
Kelly
Jeffery W
JW
Balch
William E
WE
D000682:Amyloid / Q000096:biosynthesis*; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D005109:Extracellular Matrix / Q000502:physiology; D018260:Gelsolin / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D053511:Matrix Metalloproteinase 14; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000502:physiology*; D051379:Mice; D010446:Peptide Fragments / Q000096:biosynthesis
D000682:Amyloid; D018260:Gelsolin; C507096:Mmp14 protein, mouse; D010446:Peptide Fragments; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D053511:Matrix Metalloproteinase 14