5FAF

N184K pathological variant of gelsolin domain 2 (orthorhombic form)

5FAF の概要

• エントリーDOI: 10.2210/pdb5faf/pdb
• 関連するPDBエントリー: 1KCQ
• 分子名称: Gelsolin, CALCIUM ION, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: amyloidosis, calcium, mutation, actin, 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: 13668.11

構造登録者

Boni, F.,Milani, M.,Ricagno, s.,Bolognesi, M.,de Rosa, M. (登録日: 2015-12-11, 公開日: 2016-10-05, 最終更新日: 2024-10-23)

主引用文献

Boni, F.,Milani, M.,Porcari, R.,Barbiroli, A.,Ricagno, S.,de Rosa, M.
Molecular basis of a novel renal amyloidosis due to N184K gelsolin variant.
Sci Rep, 6:33463-33463, 2016

PubMed Abstract: Mutations in gelsolin are responsible for a systemic amyloidosis first described in 1969. Until recently, the disease was associated with two substitutions of the same residue, leading to the loss of the calcium binding site. Novel interest arose in 2014 when the N184K variant of the protein was identified as the etiological agent of a novel kidney-localized amyloidosis. Here we provide a first rationale for N184K pathogenicity. We show that the mutation induces a destabilization of gelsolin second domain, without compromising its calcium binding capacity. X-ray data combined with molecular dynamics simulations demonstrates that the primary source of the destabilization is a loss of connectivity in proximity of the metal. Such rearrangement of the H-bond network does not have a major impact on the overall fold of the domain, nevertheless, it increases the flexibility of a stretch of the protein, which is consequently processed by furin protease. Overall our data suggest that the N184K variant is subjected to the same aberrant proteolytic events responsible for the formation of amyloidogenic fragments in the previously characterized mutants. At the same time our data suggest that a broader number of mutations, unrelated to the metal binding site, can lead to a pathogenic phenotype.

PubMed: 27633054
DOI: 10.1038/srep33463

実験手法

X-RAY DIFFRACTION (1.05 Å)