This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.
Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.
1kcq
From Proteopedia
|
Human Gelsolin Domain 2 with a Cd2+ bound
Contents |
Overview
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.
Disease
Known disease associated with this structure: Amyloidosis, Finnish type OMIM:[137350]
About this Structure
1KCQ is a Single protein structure of sequence from Homo sapiens with CD as ligand. Full crystallographic information is available from OCA.
Reference
Loss of a metal-binding site in gelsolin leads to familial amyloidosis-Finnish type., Kazmirski SL, Isaacson RL, An C, Buckle A, Johnson CM, Daggett V, Fersht AR, Nat Struct Biol. 2002 Feb;9(2):112-6. PMID:11753432
Page seeded by OCA on Mon Nov 12 17:49:55 2007
