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TitleStructure and dynamics of GAD65 in complex with an autoimmune polyendocrine syndrome type 2-associated autoantibody.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 2275, Year 2025
Publish dateMar 7, 2025
AuthorsSusanne H D Ständer / Cyril F Reboul / Sarah N Le / Daniel E Williams / Peter G Chandler / Mauricio G S Costa / David E Hoke / John D T Jimma / James Fodor / Gustavo Fenalti / Stuart I Mannering / Benjamin T Porebski / Peter Schofield / Daniel Christ / Malcolm Buckle / Sheena McGowan / Dominika Elmlund / Kasper D Rand / Ashley M Buckle /
PubMed AbstractThe enzyme glutamate decarboxylase (GAD) produces the neurotransmitter GABA, using pyridoxal-5'-phosphate (PLP). GAD exists as two isoforms, GAD65 and GAD67. Only GAD65 acts as a major autoantigen, ...The enzyme glutamate decarboxylase (GAD) produces the neurotransmitter GABA, using pyridoxal-5'-phosphate (PLP). GAD exists as two isoforms, GAD65 and GAD67. Only GAD65 acts as a major autoantigen, frequently implicated in type 1 diabetes and other autoimmune diseases. Here we characterize the structure and dynamics of GAD65 and its interaction with the autoimmune polyendocrine syndrome type 2-associated autoantibody b96.11. Using hydrogen-deuterium exchange mass spectrometry (HDX), X-ray crystallography, cryo-electron microscopy, and computational approaches, we examine the conformational dynamics of apo- and holoGAD65 and the GAD65-autoantibody complex. HDX reveals local dynamics accompanying autoinactivation, with the catalytic loop promoting collective motions at the CTD-PLP domain interface. In the GAD65-b96.11 complex, heavy chain CDRs dominate the interaction, with a long CDRH3 bridging the GAD65 dimer via electrostatic interactions with the PEVKEKmotif. This bridging links structural elements controlling GAD65's conformational flexibility to its autoantigenicity. Thus, intrinsic dynamics, rather than sequence differences within epitopes, appear to be responsible for the contrasting autoantigenicities of GAD65 and GAD67. Our findings elucidate the structural and dynamic factors that govern the varying autoantibody reactivities of GAD65 and GAD67, offering a revised rationale for the autoimmune response to GAD65.
External linksNat Commun / PubMed:40055307 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.6 - 7.3 Å
Structure data

23603

7lz6

EMDB-23603, PDB-7lz6:
The Cryo-EM structure of a complex between GAD65 and b96.11 Fab
Method: EM (single particle) / Resolution: 7.3 Å

PDB-9d7y:
Crystal structure of scFv corresponding to human autoantibody b96.11
Method: X-RAY DIFFRACTION / Resolution: 2.6 Å

Chemicals

ChemComp-SO4:
SULFATE ION

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / Neurotransmitter biosynthesis / Autoantibody / autoantigen / type 1 diabetes / stiff person syndrome / GABA

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