2. Academic Validation
  3. Structure of human lysosomal acid α-glucosidase-a guide for the treatment of Pompe disease

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

  • Nat Commun. 2017 Oct 24;8(1):1111. doi: 10.1038/s41467-017-01263-3.
Véronique Roig-Zamboni 1,  Beatrice Cobucci-Ponzano 2,  Roberta Iacono 2,  Maria Carmina Ferrara 2,  Stanley Germany 1,  Yves Bourne 1,  Giancarlo Parenti 3 4,  Marco Moracci 2 5,  Gerlind Sulzenbacher 6
Affiliations

Affiliations

  • 1 Centre National de la Recherche Scientifique (CNRS), Aix-Marseille Univ, AFMB, 163 Avenue de Luminy, 13288, Marseille, France.
  • 2 Institute of Biosciences and Bioresources, National Research Council of Italy, Via P. Castellino 111, 80131, Naples, Italy.
  • 3 Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, Pozzuoli, 80078, Naples, Italy.
  • 4 Department of Translational Medical Sciences, Federico II University, Via Pansini 5, 80131, Naples, Italy.
  • 5 Department of Biology, Federico II University, Complesso Universitario di Monte S. Angelo, Via Cintia 21, 80126, Naples, Italy.
  • 6 Centre National de la Recherche Scientifique (CNRS), Aix-Marseille Univ, AFMB, 163 Avenue de Luminy, 13288, Marseille, France. Gerlind.Sulzenbacher@afmb.univ-mrs.fr.
PMID: 29061980 DOI: 10.1038/s41467-017-01263-3
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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