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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Roig-Zamboni V,Cobucci-Ponzano B,Iacono R,Ferrara MC,Germany S,Bourne Y,Parenti G,Moracci M,Sulzenbacher Gdoi
10.1038/s41467-017-01263-3subject
Has Abstractpub_date
2017-10-24 00:00:00pages
1111issue
1issn
2041-1723pii
10.1038/s41467-017-01263-3journal_volume
8pub_type
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