Ca2+ binding protects against gelsolin amyloidosis.
Amyloid diseases occur when native or mutant polypeptides misfold and aggregate to form deposits in the extracellular space. There are at least 20 proteins associated with amyloid diseases, including the well-known amyloid-beta peptide that is the causative agent for Alzheimer's disease (AD). This review describes familial amyloidosis of Finnish type (FAF), an amyloid disease caused by mutations in plasma gelsolin, a secreted protein that contains multiple Ca2+-binding domains. The FAF mutations result in a loss of the Ca2+-binding site in domain 2 of plasma gelsolin. The resulting decreased stability gives rise to susceptibility to the protease furin in the Golgi. Furin cleavage generates a secreted fragment that undergoes a second proteolytic event in the extracellular matrix to produce a peptide that self-assembles into amyloid plaques. Thus, Ca2+ binding in native plasma gelsolin protects against amyloid disease.
Page
Lesley J
LJ
Department of Cell Biology, Institute for Childhood and Neglected Diseases, The Scripps Research Institute MB6, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. ljpage@scripps.edu
Huff
Mary E
ME
Kelly
Jeffery W
JW
Balch
William E
WE
D028226:Amyloidosis, Familial / Q000209:etiology* / Q000235:genetics; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D045683:Furin / Q000378:metabolism; D018260:Gelsolin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation
D018260:Gelsolin; D045683:Furin; D002118:Calcium