Journal
EMBO JOURNAL
Volume 20, Issue 22, Pages 6277-6287Publisher
OXFORD UNIV PRESS
DOI: 10.1093/emboj/20.22.6277
Keywords
amyloid; calcium; familial amyloidosis of Finnish type; furin; gelsolin
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Funding
- NIDDK NIH HHS [R01 DK046335, DK46335, R37 DK046335] Funding Source: Medline
- NIGMS NIH HHS [GM33301, GM42336, R01 GM033301, R01 GM042336] Funding Source: Medline
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Hereditary familial amyloidosis of Finnish type (FAF) leading to amyloid in the peripheral and central nervous systems stems from deposition of a 71 residue fragment generated from the D187N/Y variants of plasma gelsolin by two sequential endoproteolytic events. We identify the protease accomplishing the first cleavage as furin, a proprotein convertase. Endoproteolysis of plasma gelsolin occurs in the trans-Golgi network due to the inability of the FAF variants to bind and be stabilized by Ca2+. Secretion and processing of the FAF variants by furin can be uncoupled by blocking the convergence of the exocytic pathway transporting plasma gelsolin and the endocytic recycling of furin. We propose that coincidence of membrane trafficking pathways contributes to the development of proteolysis-initiated amyloid disease.
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