Structural characterization of the mechanism through which human glutamic acid decarboxylase auto-activates
Imbalances in GABA (γ-aminobutyric acid) homoeostasis underlie psychiatric and movement disorders. The ability of the 65 kDa isoform of GAD (glutamic acid decarboxylase), GAD65, to control synaptic GABA levels is influenced through its capacity to auto-inactivate. In contrast,...
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Portland Press, Biochemical Society
2013-01-01
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doaj-8e49de032abc453a98cb1137eab39b782020-11-24T20:44:30ZengPortland Press, Biochemical SocietyBioscience Reports0144-84631573-49352013-01-01331e0001310.1042/BSR20120111Structural characterization of the mechanism through which human glutamic acid decarboxylase auto-activatesChristopher G. LangendorfKellie L. TuckTrevor L. G. KeyGustavo FenaltiRobert N. PikeCarlos J. RosadoAnders S. M. WongAshley M. BuckleRuby H. P. LawJames C. WhisstockImbalances in GABA (γ-aminobutyric acid) homoeostasis underlie psychiatric and movement disorders. The ability of the 65 kDa isoform of GAD (glutamic acid decarboxylase), GAD65, to control synaptic GABA levels is influenced through its capacity to auto-inactivate. In contrast, the GAD67 isoform is constitutively active. Previous structural insights suggest that flexibility in the GAD65 catalytic loop drives enzyme inactivation. To test this idea, we constructed a panel of GAD65/67 chimaeras and compared the ability of these molecules to auto-inactivate. Together, our data reveal the important finding that the C-terminal domain of GAD plays a key role in controlling GAD65 auto-inactivation. In support of these findings, we determined the X-ray crystal structure of a GAD65/67 chimaera that reveals that the conformation of the catalytic loop is intimately linked to the C-terminal domain.http://www.bioscirep.org/bsr/033/e013/bsr033e013.htmauto-inactivationcatalytic loopchimaeraC-terminal domainglutamic acid decarboxylaseX-ray crystallography |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Christopher G. Langendorf Kellie L. Tuck Trevor L. G. Key Gustavo Fenalti Robert N. Pike Carlos J. Rosado Anders S. M. Wong Ashley M. Buckle Ruby H. P. Law James C. Whisstock |
spellingShingle |
Christopher G. Langendorf Kellie L. Tuck Trevor L. G. Key Gustavo Fenalti Robert N. Pike Carlos J. Rosado Anders S. M. Wong Ashley M. Buckle Ruby H. P. Law James C. Whisstock Structural characterization of the mechanism through which human glutamic acid decarboxylase auto-activates Bioscience Reports auto-inactivation catalytic loop chimaera C-terminal domain glutamic acid decarboxylase X-ray crystallography |
author_facet |
Christopher G. Langendorf Kellie L. Tuck Trevor L. G. Key Gustavo Fenalti Robert N. Pike Carlos J. Rosado Anders S. M. Wong Ashley M. Buckle Ruby H. P. Law James C. Whisstock |
author_sort |
Christopher G. Langendorf |
title |
Structural characterization of the mechanism through which human glutamic acid decarboxylase auto-activates |
title_short |
Structural characterization of the mechanism through which human glutamic acid decarboxylase auto-activates |
title_full |
Structural characterization of the mechanism through which human glutamic acid decarboxylase auto-activates |
title_fullStr |
Structural characterization of the mechanism through which human glutamic acid decarboxylase auto-activates |
title_full_unstemmed |
Structural characterization of the mechanism through which human glutamic acid decarboxylase auto-activates |
title_sort |
structural characterization of the mechanism through which human glutamic acid decarboxylase auto-activates |
publisher |
Portland Press, Biochemical Society |
series |
Bioscience Reports |
issn |
0144-8463 1573-4935 |
publishDate |
2013-01-01 |
description |
Imbalances in GABA (γ-aminobutyric acid) homoeostasis underlie psychiatric and movement disorders. The ability of the 65 kDa isoform of GAD (glutamic acid decarboxylase), GAD65, to control synaptic GABA levels is influenced through its capacity to auto-inactivate. In contrast, the GAD67 isoform is constitutively active. Previous structural insights suggest that flexibility in the GAD65 catalytic loop drives enzyme inactivation. To test this idea, we constructed a panel of GAD65/67 chimaeras and compared the ability of these molecules to auto-inactivate. Together, our data reveal the important finding that the C-terminal domain of GAD plays a key role in controlling GAD65 auto-inactivation. In support of these findings, we determined the X-ray crystal structure of a GAD65/67 chimaera that reveals that the conformation of the catalytic loop is intimately linked to the C-terminal domain. |
topic |
auto-inactivation catalytic loop chimaera C-terminal domain glutamic acid decarboxylase X-ray crystallography |
url |
http://www.bioscirep.org/bsr/033/e013/bsr033e013.htm |
work_keys_str_mv |
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