Loss of a metal-binding site in gelsolin leads to familial amyloidosis-Finnish type

Nat Struct Biol. 2002 Feb;9(2):112-6. doi: 10.1038/nsb745.

Abstract

Mutations in domain 2 (D2, residues 151-266) of the actin-binding protein gelsolin cause familial amyloidosis-Finnish type (FAF). These mutations, D187N or D187Y, lead to abnormal proteolysis of plasma gelsolin at residues 172-173 and a second hydrolysis at residue 243, resulting in an amyloidogenic fragment. Here we present the structure of human gelsolin D2 at 1.65 A and find that Asp 187 is part of a Cd2+ metal-binding site. Two Ca2+ ions are required for a conformational transition of gelsolin to its active form. Differential scanning calorimetry (DSC) and molecular dynamics (MD) simulations suggest that the Cd2+-binding site in D2 is one of these two Ca2+-binding sites and is essential to the stability of D2. Mutation of Asp 187 to Asn disrupts Ca2+ binding in D2, leading to instabilities upon Ca2+ activation. These instabilities make the domain a target for aberrant proteolysis, thereby enacting the first step in the cascade leading to FAF.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Substitution / genetics
  • Amyloidosis, Familial / genetics*
  • Aspartic Acid / genetics
  • Aspartic Acid / metabolism
  • Binding Sites
  • Cadmium / metabolism*
  • Calcium / metabolism
  • Calorimetry, Differential Scanning
  • Computer Simulation
  • Crystallography, X-Ray
  • Finland
  • Gelsolin / chemistry
  • Gelsolin / genetics*
  • Gelsolin / metabolism*
  • Humans
  • Models, Molecular
  • Mutation / genetics*
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Thermodynamics

Substances

  • Gelsolin
  • Cadmium
  • Aspartic Acid
  • Calcium

Associated data

  • PDB/1KCQ