1kcq

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spinqualitylabelsall models 1kcq, resolution 1.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Human Gelsolin Domain 2 with a Cd2+ bound

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

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

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