Structure and dynamics of GAD65 in complex with an autoimmune polyendocrine syndrome type 2-associated autoantibody.

• Tác giả: Ashley M Buckle, Malcolm Buckle, Peter G Chandler, Daniel Christ, Mauricio G S Costa, Dominika Elmlund, Gustavo Fenalti, James Fodor, David E Hoke, John D T Jimma, Sarah N Le, Stuart I Mannering, Sheena McGowan, Benjamin T Porebski, Kasper D Rand, Cyril F Reboul, Peter Schofield, Susanne H D Ständer, Daniel E Williams
• Ngôn ngữ: eng
• Ký hiệu phân loại: 025.432 *Universal Decimal Classification
• Thông tin xuất bản: England : Nature communications , 2025
• Bộ sưu tập: NCBI
• ID: 693029

Tóm tắt

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