The molecular basis for Pompe disease revealed by the structure of human acid α-glucosidase

Pompe disease results from a defect in human acid α-glucosidase (GAA), a lysosomal enzyme that cleaves terminal α1-4 and α1-6 glucose from glycogen. In Pompe disease (also known as Glycogen Storage Disorder type II), the accumulation of undegraded glycogen in lysosomes leads to cellular dysfunction, primarily in muscle and heart tissues. Pompe disease is an active candidate of clinical research, with pharmacological chaperone therapy tested and enzyme replacement therapy approved. Despite production of large amounts of recombinant GAA annually, the structure of GAA has not been reported until now. Here, we describe the first structure of GAA, at 1.7A resolution. Three structures of GAA complexes reveal the molecular basis for the hundreds of mutations that lead to Pompe disease and for pharmacological chaperoning in the protein. The GAA structure reveals a surprising second sugar-binding site 34A from the active site, suggesting a possible mechanism for processing of large glycogen substrates. Overall, the structure will assist in the design of next-generation treatments for Pompe disease.