title: Furin initiates gelsolin familial amyloidosis in the Golgi through a defect in Ca(2+) stabilization.
abstract: 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 Ca(2+). 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.
authors.affiliation: Departments of Molecular and Cell Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Chen
authors.forename: M E
authors.initials: ME
authors.lastname: Huff
authors.forename: J
authors.initials: J
authors.lastname: Matteson
authors.forename: L
authors.initials: L
authors.lastname: Page
authors.forename: R
authors.initials: R
authors.lastname: Phillips
authors.forename: J W
authors.initials: JW
authors.lastname: Kelly
authors.forename: W E
authors.initials: WE
authors.lastname: Balch
mesh_terms: D028226:Amyloidosis, Familial / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002151:Calorimetry; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D045683:Furin; D018260:Gelsolin / Q000097:blood* / Q000378:metabolism; D014644:Genetic Variation; D006056:Golgi Apparatus / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013381:Subtilisins / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics; D013997:Time Factors; D014162:Transfection
chemical_list: D018260:Gelsolin; D013381:Subtilisins; D045683:Furin; D002118:Calcium