Article abstract
Nature Structural & Molecular Biology 14, 280 - 286 (2007)
Published online: 25 March 2007 | doi:10.1038/nsmb1228
GABA production by glutamic acid decarboxylase is regulated by a dynamic catalytic loop
Gustavo Fenalti1,6, Ruby H P Law1,6, Ashley M Buckle1,6, Christopher Langendorf1, Kellie Tuck2, Carlos J Rosado1, Noel G Faux1, Khalid Mahmood1, Christiane S Hampe3, J Paul Banga4, Matthew Wilce1, Jason Schmidberger1, Jamie Rossjohn1, Ossama El-Kabbani5, Robert N Pike1, A Ian Smith1, Ian R Mackay1, Merrill J Rowley1 & James C Whisstock1
Abstract
Gamma-aminobutyric acid (GABA) is synthesized by two isoforms of the pyridoxal 5'-phosphate–dependent enzyme glutamic acid decarboxylase (GAD65 and GAD67). GAD67 is constitutively active and is responsible for basal GABA production. In contrast, GAD65, an autoantigen in type I diabetes, is transiently activated in response to the demand for extra GABA in neurotransmission, and cycles between an active holo form and an inactive apo form. We have determined the crystal structures of N-terminal truncations of both GAD isoforms. The structure of GAD67 shows a tethered loop covering the active site, providing a catalytic environment that sustains GABA production. In contrast, the same catalytic loop is inherently mobile in GAD65. Kinetic studies suggest that mobility in the catalytic loop promotes a side reaction that results in cofactor release and GAD65 autoinactivation. These data reveal the molecular basis for regulation of GABA homeostasis.
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Melbourne, VIC 3800, Australia.
- School of Chemistry, Monash University, Melbourne VIC 3800, Australia.
- Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98195, USA.
- King's College London School of Medicine, Division of Gene and Cell Based Therapy, Denmark Hill Campus, London SE5 9PJ, UK.
- Victorian College of Pharmacy, Monash University, Parkville, VIC 3052, Australia.
- These authors contributed equally to this work.
Correspondence to: James C Whisstock1 e-mail: james.whisstock@med.monash.edu.au
Correspondence to: Merrill J Rowley1 e-mail: merrill.rowley@med.monash.edu.au
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