1KCQ

Human Gelsolin Domain 2 with a Cd2+ bound

1KCQ の概要

• エントリーDOI: 10.2210/pdb1kcq/pdb
• 分子名称: GELSOLIN, CADMIUM ION (3 entities in total)
• 機能のキーワード: alpha-beta structure, actin-binding protein, familial amyloidosis--finnish type, cadmium binding, metal binding, structural protein
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Isoform 2: Cytoplasm, cytoskeleton. Isoform 1: Secreted: P06396
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 12042.61

構造登録者

Kazmirski, S.L.,Isaacson, R.L.,An, C.,Buckle, A.,Johnson, C.M.,Daggett, V.,Fersht, A.R. (登録日: 2001-11-09, 公開日: 2002-01-04, 最終更新日: 2023-08-16)

主引用文献

Kazmirski, S.L.,Isaacson, R.L.,An, C.,Buckle, A.,Johnson, C.M.,Daggett, V.,Fersht, A.R.
Loss of a metal-binding site in gelsolin leads to familial amyloidosis-Finnish type.
Nat.Struct.Biol., 9:112-116, 2002

PubMed 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.

PubMed: 11753432
DOI: 10.1038/nsb745

実験手法

X-RAY DIFFRACTION (1.65 Å)