Furin initiates gelsolin familial amyloidosis in the Golgi through a defect in Ca2+ stabilization
Furin initiates gelsolin familial amyloidosis in the Golgi through a defect in Ca2+ stabilization
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DOI：
10.1093/emboj/20.22.6277
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发表时间：
2001-11-15
期刊：
影响因子：
11.4
通讯作者：
Balch, WE
中科院分区：
文献类型：
--
作者：
Chen, CD;Huff, ME;Balch, WE
遗传性芬兰型家族性淀粉样变性(FAF)导致周围和中枢神经系统淀粉样变性的原因是血浆明胶蛋白D187N/Y变异产生的71个残基片段通过两次连续的内蛋白降解事件而沉积。我们确定完成第一次切割的蛋白水解酶是FURIN，一种原蛋白转换酶。由于Faf变异体不能结合并被钙离子稳定，血浆明胶蛋白的内切作用发生在跨高尔基体网络中。通过阻断转运血浆明胶蛋白的胞外途径的收敛和呋喃的胞内循环，可以解偶联呋喃对Faf异构体的分泌和加工。我们认为，膜转运途径的重合有助于蛋白水解性淀粉样蛋白疾病的发展。
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.