Structural characterization of the mechanism through which human glutamic acid decarboxylase auto-activates

Christopher Grant Langendorf, Kellie Louise Tuck, Trevor Key, Gustavo Fenalti, Robert Neil Pike, Carlos Joaquim Rosado, Anders SM Wong, Ashley Maurice Buckle, Ruby Hong Ping Law, James Whisstock

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Imbalances in GABA (gamma-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.
Original languageEnglish
Pages (from-to)137 - 149
Number of pages13
JournalBioscience Reports
Volume33
Issue number1 (Art # A13)
DOIs
Publication statusPublished - 2013

Cite this

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title = "Structural characterization of the mechanism through which human glutamic acid decarboxylase auto-activates",
abstract = "Imbalances in GABA (gamma-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.",
author = "Langendorf, {Christopher Grant} and Tuck, {Kellie Louise} and Trevor Key and Gustavo Fenalti and Pike, {Robert Neil} and Rosado, {Carlos Joaquim} and Wong, {Anders SM} and Buckle, {Ashley Maurice} and Law, {Ruby Hong Ping} and James Whisstock",
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volume = "33",
pages = "137 -- 149",
journal = "Bioscience Reports",
issn = "0144-8463",
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Structural characterization of the mechanism through which human glutamic acid decarboxylase auto-activates. / Langendorf, Christopher Grant; Tuck, Kellie Louise; Key, Trevor; Fenalti, Gustavo; Pike, Robert Neil; Rosado, Carlos Joaquim; Wong, Anders SM; Buckle, Ashley Maurice; Law, Ruby Hong Ping; Whisstock, James.

In: Bioscience Reports, Vol. 33, No. 1 (Art # A13), 2013, p. 137 - 149.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Tuck, Kellie Louise

AU - Key, Trevor

AU - Fenalti, Gustavo

AU - Pike, Robert Neil

AU - Rosado, Carlos Joaquim

AU - Wong, Anders SM

AU - Buckle, Ashley Maurice

AU - Law, Ruby Hong Ping

AU - Whisstock, James

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AB - Imbalances in GABA (gamma-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.

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