4S10

Gelsolin nanobody shielding mutant plasma gelsolin from furin proteolysis

4S10 の概要

• エントリーDOI: 10.2210/pdb4s10/pdb
• 関連するPDBエントリー: 4S11
• 分子名称: GELSOLIN NANOBODY, Gelsolin, CALCIUM ION, ... (4 entities in total)
• 機能のキーワード: gelsolin-like, actin-binding, metal binding protein-immune system complex, metal binding protein/immune system
• 由来する生物種: Lama glama; 詳細
• 細胞内の位置: Isoform 2: Cytoplasm, cytoskeleton. Isoform 1: Secreted: P06396
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 50431.58

構造登録者

Wongsantichon, J.,Robinson, R.C.,Gettemans, J. (登録日: 2015-01-07, 公開日: 2015-06-03, 最終更新日: 2024-11-20)

主引用文献

Van Overbeke, W.,Wongsantichon, J.,Everaert, I.,Verhelle, A.,Zwaenepoel, O.,Loonchanta, A.,Burtnick, L.D.,De Ganck, A.,Hochepied, T.,Haigh, J.,Cuvelier, C.,Derave, W.,Robinson, R.C.,Gettemans, J.
An ER-directed gelsolin nanobody targets the first step in amyloid formation in a gelsolin amyloidosis mouse model.
Hum.Mol.Genet., 24:2492-2507, 2015

PubMed Abstract: Hereditary gelsolin amyloidosis is an autosomal dominantly inherited amyloid disorder. A point mutation in the GSN gene (G654A being the most common one) results in disturbed calcium binding by the second gelsolin domain (G2). As a result, the folding of G2 is hampered, rendering the mutant plasma gelsolin susceptible to a proteolytic cascade. Consecutive cleavage by furin and MT1-MMP-like proteases generates 8 and 5 kDa amyloidogenic peptides that cause neurological, ophthalmological and dermatological findings. To this day, no specific treatment is available to counter the pathogenesis. Using GSN nanobody 11 as a molecular chaperone, we aimed to protect mutant plasma gelsolin from furin proteolysis in the trans-Golgi network. We report a transgenic, GSN nanobody 11 secreting mouse that was used for crossbreeding with gelsolin amyloidosis mice. Insertion of the therapeutic nanobody gene into the gelsolin amyloidosis mouse genome resulted in improved muscle contractility. X-ray crystal structure determination of the gelsolin G2:Nb11 complex revealed that Nb11 does not directly block the furin cleavage site. We conclude that nanobodies can be used to shield substrates from aberrant proteolysis and this approach might establish a novel therapeutic strategy in amyloid diseases.

PubMed: 25601851
DOI: 10.1093/hmg/ddv010

実験手法

X-RAY DIFFRACTION (2.614 Å)