ArticleHuman molecular genetics2015
Structural basis of glycogen branching enzyme deficiency and pharmacologic rescue by rational peptide design.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 89 citations in OpenAlex.
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- Prediction of the Prognosis and Treatment Responses Based on the Characteristics of Disulfidptosis-Related Genes in Patients with Cervical Squamous Cell Carcinoma and Endocervical AdenocarcinomaEndocrine, metabolic & immune disorders drug targets · 2026Article
- Autosomal Recessive Cerebellar Ataxias: Translating Genes to Therapies.Annals of neurology · 2025Review
- Molecular architecture and catalytic mechanism of human glycogen debranching enzyme.Nature communications · 2025Article
- Branched Polymer Architecture for Modulating Interactions in Material-Bio Interface.Tissue engineering and regenerative medicine · 2025Review
- Elucidation of the noncovalent interactions driving enzyme activity guides branching enzyme engineering for α-glucan modification.Nature communications · 2024Article
- The Autophagic Activator GHF-201 Can Alleviate Pathology in a Mouse Model and in Patient Fibroblasts of Type III Glycogenosis.Biomolecules · 2024Article
- WTAP/IGF2BP3-mediated GBE1 expression accelerates the proliferation and enhances stemness in pancreatic cancer cells via upregulating c-Myc.Cellular & molecular biology letters · 2024Article
- Atg45 is an autophagy receptor for glycogen, a non-preferred cargo of bulk autophagy in yeast.iScience · 2024Article
- Compartmentalization proteomics revealed endolysosomal protein network changes in a goat model of atrial fibrillation.iScience · 2024Article
- Natural history study of hepatic glycogen storage disease type IV and comparison to Gbe1ys/ys model.JCI insight · 2024Article
- Identification of Novel and Recurrent Variants inJournal of clinical medicine · 2024Article
- Article
- Drosophila embryos spatially sort their nutrient stores to facilitate their utilization.Development (Cambridge, England) · 2023Article
- An Unusual Case of Neonatal Hypotonia and Femur Fracture: Neuromuscular Variant of Glycogen Storage Disease Type IV.Children (Basel, Switzerland) · 2023Article
- The Structure of Maltooctaose-BoundMolecules (Basel, Switzerland) · 2023Article
- Stochastic modelling of a three-dimensional glycogen granule synthesis and impact of the branching enzyme.PLoS computational biology · 2023Article
- A Broad Characterization of Glycogen Storage Disease IV Patients: A Clinical, Genetic, and Histopathological Study.Biomedicines · 2023Article
- Lysosomal glycogen accumulation in Pompe disease results in disturbed cytoplasmic glycogen metabolism.Journal of inherited metabolic disease · 2023Article
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Authors and funding
15 authors at 6 institutions in 4 countries.
Funding
Abstract
Glycogen branching enzyme 1 (GBE1) plays an essential role in glycogen biosynthesis by generating α-1,6-glucosidic branches from α-1,4-linked glucose chains, to increase solubility of the glycogen polymer. Mutations in the GBE1 gene lead to the heterogeneous early-onset glycogen storage disorder type IV (GSDIV) or the late-onset adult polyglucosan body disease (APBD). To better understand this essential enzyme, we crystallized human GBE1 in the apo form, and in complex with a tetra- or hepta-saccharide. The GBE1 structure reveals a conserved amylase core that houses the active centre for the branching reaction and harbours almost all GSDIV and APBD mutations. A non-catalytic binding cleft, proximal to the site of the common APBD mutation p.Y329S, was found to bind the tetra- and hepta-saccharides and may represent a higher-affinity site employed to anchor the complex glycogen substrate for the branching reaction. Expression of recombinant GBE1-p.Y329S resulted in drastically reduced protein yield and solubility compared with wild type, suggesting this disease allele causes protein misfolding and may be amenable to small molecule stabilization. To explore this, we generated a structural model of GBE1-p.Y329S and designed peptides ab initio to stabilize the mutation. As proof-of-principle, we evaluated treatment of one tetra-peptide, Leu-Thr-Lys-Glu, in APBD patient cells. We demonstrate intracellular transport of this peptide, its binding and stabilization of GBE1-p.Y329S, and 2-fold increased mutant enzymatic activity compared with untreated patient cells. Together, our data provide the rationale and starting point for the screening of small molecule chaperones, which could become novel therapies for this disease.
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