Structure of human lysosomal acid α-glucosidase–a guide for the treatment of Pompe disease - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Nature Communications Année : 2017

Structure of human lysosomal acid α-glucosidase–a guide for the treatment of Pompe disease

Résumé

Pompe disease, a rare lysosomal storage disease caused by deficiency of the lysosomal acid α-glucosidase (GAA), is characterized by glycogen accumulation, triggering severe secondary cellular damage and resulting in progressive motor handicap and premature death. Numerous disease-causing mutations in the gaa gene have been reported, but the structural effects of the pathological variants were unknown. Here we present the high-resolution crystal structures of recombinant human GAA (rhGAA), the standard care of Pompe disease. These structures portray the unbound form of rhGAA and complexes thereof with active site-directed inhibitors, providing insight into substrate recognition and the molecular framework for the rationalization of the deleterious effects of disease-causing mutations. Furthermore, we report the structure of rhGAA in complex with the allosteric pharmacological chaperone N-acetylcysteine, which reveals the stabilizing function of this chaperone at the structural level.
Fichier principal
Vignette du fichier
s41467-017-01263-3.pdf (2.2 Mo) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte
Loading...

Dates et versions

hal-01802847 , version 1 (08-06-2018)

Identifiants

Citer

Veronique Roig-Zamboni, Beatrice Cobucci-Ponzano, Roberta Iacono, Maria Carmina Ferrara, Stanley Germany, et al.. Structure of human lysosomal acid α-glucosidase–a guide for the treatment of Pompe disease. Nature Communications, 2017, 8, pp.1111. ⟨10.1038/s41467-017-01263-3⟩. ⟨hal-01802847⟩
77 Consultations
89 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More