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

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.

• Authors: Steven L Kazmirski, Rivka L Isaacson, Chahm An, Ashley Buckle, Christopher M Johnson, Valerie Daggett, Alan R Fersht
• Journal: Nature structural biology (Nat Struct Biol) Vol. 9 Issue 2 Pg. 112-6 (Feb 2002) ISSN: 1072-8368 [Print] United States
• PMID: 11753432 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Gelsolin
• Cadmium
• Aspartic Acid
• Calcium

Topics

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