ArticleProceedings of the National Academy of Sciences of the United States of America2014
Cofactor-dependent conformational heterogeneity of GAD65 and its role in autoimmunity and neurotransmitter homeostasis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 41 citations in OpenAlex.
- Molecular Portrait of Autoantigens in Type 1 Diabetes.Biomolecules · 2025Review
- The CRISPR-Cas9 knockout DDC SH-SY5Y in vitro model for AADC deficiency provides insight into the pathogenicity of R347Q and L353P variants: a cross-sectional structural and functional analysis.The FEBS journal · 2025Article
- Structure and dynamics of GAD65 in complex with an autoimmune polyendocrine syndrome type 2-associated autoantibody.Nature communications · 2025Article
- Insomnia treatment based on the regulation of the GABAergic system: traditional Chinese medicine perspectives and therapeutic approaches.Frontiers in neuroscience · 2025Review
- Long-lived proteins and DNA as candidate predictive biomarkers for tissue associated diseases.iScience · 2024Article
- The role of GABA in type 1 diabetes.Frontiers in endocrinology · 2024Review
- Human aromatic amino acid decarboxylase is an asymmetric and flexible enzyme: Implication in aromatic amino acid decarboxylase deficiency.Protein science : a publication of the Protein Society · 2023Article
- Two putative glutamate decarboxylases of Streptococcus pneumoniae as possible antigens for the production of anti-GAD65 antibodies leading to type 1 diabetes mellitus.International microbiology : the official journal of the Spanish Society for Microbiology · 2023Article
- Deletion of Crtc1 leads to hippocampal neuroenergetic impairments associated with depressive-like behavior.Molecular psychiatry · 2022Article
- The novel P330L pathogenic variant of aromatic amino acid decarboxylase maps on the catalytic flexible loop underlying its crucial role.Cellular and molecular life sciences : CMLS · 2022Article
- The role of GABA in islet function.Frontiers in endocrinology · 2022Review
- Glutamic Acid Decarboxylase Concentration Changes in Response to Stress and Altered Availability of Glutamic Acid in Rabbit (Animals : an open access journal from MDPI · 2021Article
- Exposing the distinctive modular behavior of β-strands and α-helices in folded proteins.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Developmental GAD2 Expression Reveals Progenitor-like Cells with Calcium Waves in Mammalian Crista Ampullaris.iScience · 2020Article
- Mechanism and effects of pulsatile GABA secretion from cytosolic pools in the human beta cell.Nature metabolism · 2019Article
- [Research advances in pathogenesis of attention deficit hyperactivity disorder].Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics · 2018Article
- Synthesis and Deployment of an Elusive Fluorovinyl Cation Equivalent: Access to Quaternary α-(1'-Fluoro)vinyl Amino Acids as Potential PLP Enzyme Inactivators.Journal of the American Chemical Society · 2017Article
- Islet Autoantibodies.Current diabetes reports · 2016Review
- Conformational Equilibrium of CDK/Cyclin Complexes by Molecular Dynamics with Excited Normal Modes.Biophysical journal · 2015Article
- Compartmentalization of GABA synthesis by GAD67 differs between pancreatic beta cells and neurons.PloS one · 2015Article
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Authors and funding
20 authors at 9 institutions in 4 countries.
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No grant is acknowledged in the PubMed record.
Abstract
The human neuroendocrine enzyme glutamate decarboxylase (GAD) catalyses the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) using pyridoxal 5'-phosphate as a cofactor. GAD exists as two isoforms named according to their respective molecular weights: GAD65 and GAD67. Although cytosolic GAD67 is typically saturated with the cofactor (holoGAD67) and constitutively active to produce basal levels of GABA, the membrane-associated GAD65 exists mainly as the inactive apo form. GAD65, but not GAD67, is a prevalent autoantigen, with autoantibodies to GAD65 being detected at high frequency in patients with autoimmune (type 1) diabetes and certain other autoimmune disorders. The significance of GAD65 autoinactivation into the apo form for regulation of neurotransmitter levels and autoantibody reactivity is not understood. We have used computational and experimental approaches to decipher the nature of the holo → apo conversion in GAD65 and thus, its mechanism of autoinactivation. Molecular dynamics simulations of GAD65 reveal coupling between the C-terminal domain, catalytic loop, and pyridoxal 5'-phosphate-binding domain that drives structural rearrangement, dimer opening, and autoinactivation, consistent with limited proteolysis fragmentation patterns. Together with small-angle X-ray scattering and fluorescence spectroscopy data, our findings are consistent with apoGAD65 existing as an ensemble of conformations. Antibody-binding kinetics suggest a mechanism of mutually induced conformational changes, implicating the flexibility of apoGAD65 in its autoantigenicity. Although conformational diversity may provide a mechanism for cofactor-controlled regulation of neurotransmitter biosynthesis, it may also come at a cost of insufficient development of immune self-tolerance that favors the production of GAD65 autoantibodies.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.