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Gelsolin is a dynamic actin-filament-severing and -capping protein (1) capable of the demolition of the actin cytoskeleton. Gelsolin undergoes large conformational changes on binding calcium and actin, transformations that can be reversed on interaction with phosphatidylinositol 4,5-bisphosphate (PIP2) and the removal of calcium. This structural plasticity goes askew in familial amyloidosis (Finnish type) (FAF), where a single amino acid mutation (2), at residue 187, produces an aberrant, protease-sensitive molecule. A series of protease cleavages follow that result in a fragment of gelsolin domain 2 (residues 173–243; Fig. 1) that spontaneously associates into amyloid fibrils. These fibrils are deposited mainly in the facial regions of FAF sufferers, producing physical and cosmetic dysfunction. Ratnaswamy et al. (3) provide insight into the mechanism of FAF-gelsolin degeneration and, hence, the progression of this disease, by assessing the conformational stability of the FAF mutant domain 2 in comparison with that of the wild type. The structure of the second domain of gelsolin (G2) in the absence of calcium. Residue 187 is the mutation site in FAF, and residues 173–243 (gold) comprise the amyloid fragment. Fersht and coworkers studied a fragment comprising residues 151–266 (green and gold) and Ratnaswamy et al. examined the entire G2, residues 134–266 (blue, green and gold) (3, 5). Theories of the structural disintegration of FAF-gelsolin abound. On elucidating the structure of nonactivated gelsolin (4), we proposed that the network of interactions formed by residue D187 (the mutation site in FAF) stabilizes the central β-sheet of gelsolin domain 2 (G2). Hence, in FAF G2, this β-sheet is relatively destabilized, allowing the structure to open up and allow protease cleavage. This hypothesis, whereby the FAF G2 unfolds to some degree before cleavage can take place, will be referred to as the disintegration …

The disintegration of a molecule: The role of gelsolin in FAF, familial amyloidosis (Finnish type)