Ca2+ binding protects against gelsolin amyloidosis

Biochemical and Biophysical Research Communications
Lesley J PageWilliam E Balch

Abstract

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.

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Citations

May 15, 2009·The American Journal of the Medical Sciences·Mohammadali M ShojaSari Kiuru-Enari
Mar 1, 2012·Critical Reviews in Biochemistry and Molecular Biology·James P SolomonJeffery W Kelly

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