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

• DOI: 10.1073/pnas.1902189116
• Publication Date: 2019-06-27T01:55:25Z
• Authors: Habiba Zorgati; Mårten Larsson; Weitong Ren; Adelene Y. L. Sim; Jan Gettemans; Jonathan M. Grimes; Wenfei Li; Robert C. Robinson
• Keywords: Furin; Gelsolin; Cleavage (geology)

In the disease familial amyloidosis, Finnish type (FAF), also known as AGel amyloidosis (AGel), mechanism by which point mutations in calcium-regulated actin-severing protein gelsolin lead to furin cleavage is not understood intact protein. Here, we provide a structural and biochemical characterization of FAF variants. X-ray crystallography structures mutant gelsolins demonstrate that do significantly disrupt calcium-free conformations gelsolin. Small-angle X-ray–scattering (SAXS) studies indicate calcium-binding site mutants are slower activate, whereas G167R efficient wild type. Actin-regulating at pH (6.5) show functional, suggesting they adopt relatively normal active conformations. Deletion domains leads sensitization cleavage, nanobody-binding protects against cleavage. These data instability second domain (G2), since loss or gain G2-stabilizing interactions impacts efficiency furin. To this principle, engineered non-FAF G3 G2-G3 interface calcium-activated structure. led increased We carried out molecular dynamics (MD) simulations on fragments All showed an increase distance between center masses 2 (G2 G3). Since covers G2 gelsolin, suggests destabilization critical step