The role of gelsolin domain 3 in familial amyloidosis (Finnish type)

In the disease familial amyloidosis, Finnish type (FAF) the mechanism by which point mutations in gelsolin domain 2 (G2) lead to furin cleavage is not understood for the intact protein. Here, we determine that FAF mutants adopt similar conformations to the wild-type protein. However, the mutations appear to affect the dynamics of domain:domain interactions. Thus, proper domain:domain interactions are needed to protect G2 from protease cleavage. We make mutations in the following domain (G3) that functionally mimic the FAF mutations in G2. We conclude that G2 is on the limits of stability, and perturbations that affect domain:domain stabilizing interactions tip the balance toward cleavage. These data explain how multiple FAF mutations give rise to amyloid formation.