Structure of human lysosomal acid α-glucosidase-a guide for the treatment of Pompe disease - Archive ouverte HAL Access content directly
Journal Articles Nature Communications Year : 2017

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

Beatrice Cobucci-Ponzano
Roberta Iacono
Maria Carmina Ferrara
  • Function : Author
Stanley Germany
  • Function : Author
Yves Bourne
Giancarlo Parenti
  • Function : Author
Marco Moracci

Abstract

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.
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Dates and versions

hal-03158352 , version 1 (03-03-2021)

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Véronique 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, ⟨10.1038/s41467-017-01263-3⟩. ⟨hal-03158352⟩
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