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

Véronique Roig-Zamboni, Beatrice Cobucci-Ponzano, Roberta Iacono, Maria Carmina Ferrara, Stanley Germany, Yves Bourne, Giancarlo Parenti, Marco Moracci and Gerlind Sulzenbacher ()
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Véronique Roig-Zamboni: Aix-Marseille Univ, AFMB
Beatrice Cobucci-Ponzano: National Research Council of Italy
Roberta Iacono: National Research Council of Italy
Maria Carmina Ferrara: National Research Council of Italy
Stanley Germany: Aix-Marseille Univ, AFMB
Yves Bourne: Aix-Marseille Univ, AFMB
Giancarlo Parenti: Via Campi Flegrei 34
Marco Moracci: National Research Council of Italy
Gerlind Sulzenbacher: Aix-Marseille Univ, AFMB

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01263-3

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