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

Véronique Roig-Zamboni (1) , Beatrice Cobucci-Ponzano , Roberta Iacono , Maria Carmina Ferrara , Stanley Germany , Yves Bourne , Giancarlo Parenti , Marco Moracci , Gerlind Sulzenbacher (1)

1 AFMB - Architecture et fonction des macromolécules biologiques

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.

Domaines: Sciences du Vivant [q-bio]

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⟩