6XG7

1.3 A Resolution Structure of the of the NHL Repeat Region of D. melanogaster Thin

6XG7 の概要

• エントリーDOI: 10.2210/pdb6xg7/pdb
• 分子名称: Thin, isoform D, SULFATE ION, TETRAETHYLENE GLYCOL, ... (4 entities in total)
• 機能のキーワード: protein-protein interaction, beta-propeller, limb girdle muscular dystrophy type 2h, protein binding
• 由来する生物種: Drosophila melanogaster (Fruit fly)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33469.93

構造登録者

Kashipathy, M.M.,Lovell, S.,Battaile, K.P.,Bawa, S.,Geisbrecht, E.R. (登録日: 2020-06-17, 公開日: 2020-12-16, 最終更新日: 2024-10-16)

主引用文献

Bawa, S.,Gameros, S.,Baumann, K.,Brooks, D.S.,Kollhoff, J.A.,Zolkiewski, M.,Re Cecconi, A.D.,Panini, N.,Russo, M.,Piccirillo, R.,Johnson, D.K.,Kashipathy, M.M.,Battaile, K.P.,Lovell, S.,Bouyain, S.E.A.,Kawakami, J.,Geisbrecht, E.R.
Costameric integrin and sarcoglycan protein levels are altered in a Drosophila model for Limb-girdle muscular dystrophy type 2H.
Mol.Biol.Cell, 32:260-273, 2021

PubMed Abstract: Mutations in two different domains of the ubiquitously expressed TRIM32 protein give rise to two clinically separate diseases, one of which is Limb-girdle muscular dystrophy type 2H (LGMD2H). Uncovering the muscle-specific role of TRIM32 in LGMD2H pathogenesis has proven difficult, as neurogenic phenotypes, independent of LGMD2H pathology, are present in mice. We previously established a platform to study LGMD2H pathogenesis using as a model. Here we show that LGMD2H disease-causing mutations in the NHL domain are molecularly and structurally conserved between fly and human TRIM32. Furthermore, transgenic expression of a subset of myopathic alleles (R394H, D487N, and 520fs) induce myofibril abnormalities, altered nuclear morphology, and reduced TRIM32 protein levels, mimicking phenotypes in patients afflicted with LGMD2H. Intriguingly, we also report for the first time that the protein levels of βPS integrin and sarcoglycan δ, both core components of costameres, are elevated in TRIM32 disease-causing alleles. Similarly, murine myoblasts overexpressing a catalytically inactive TRIM32 mutant aberrantly accumulate α- and β-dystroglycan and α-sarcoglycan. We speculate that the stoichiometric loss of costamere components disrupts costamere complexes to promote muscle degeneration.

PubMed: 33296226
DOI: 10.1091/mbc.E20-07-0453

実験手法

X-RAY DIFFRACTION (1.3 Å)