An autoinhibitory helix in the C-terminal region of phospholipase C-B mediates Gaq activation

Angeline M Lyon, Valerie M Tesmer, Vishan D Dhamsania, David Thal, Joanne Gutierrez, Shoaib Chowdhury, Krishna C Suddala, John K Northup, John Joseph Grubb Tesmer

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Abstract

The enzyme phospholipase C-? (PLC?) is a crucial regulator of intracellular calcium levels whose activity is controlled by heptahelical receptors that couple to members of the Gq family of heterotrimeric G proteins. We have determined atomic structures of two invertebrate homologs of PLC? (PLC21) from cephalopod retina and identified a helix from the C-terminal regulatory region that interacts with a conserved surface of the catalytic core of the enzyme. Mutations designed to disrupt the analogous interaction in human PLC?3 considerably increase basal activity and diminish stimulation by Gaq. Gaq binding requires displacement of the autoinhibitory helix from the catalytic core, thus providing an allosteric mechanism for activation of PLC?.
Original languageEnglish
Pages (from-to)999 - 1006
Number of pages8
JournalNature Structural and Molecular Biology
Volume18
Issue number9
DOIs
Publication statusPublished - 2011
Externally publishedYes

Cite this

Lyon, A. M., Tesmer, V. M., Dhamsania, V. D., Thal, D., Gutierrez, J., Chowdhury, S., ... Tesmer, J. J. G. (2011). An autoinhibitory helix in the C-terminal region of phospholipase C-B mediates Gaq activation. Nature Structural and Molecular Biology, 18(9), 999 - 1006. https://doi.org/10.1038/nsmb.2095
Lyon, Angeline M ; Tesmer, Valerie M ; Dhamsania, Vishan D ; Thal, David ; Gutierrez, Joanne ; Chowdhury, Shoaib ; Suddala, Krishna C ; Northup, John K ; Tesmer, John Joseph Grubb. / An autoinhibitory helix in the C-terminal region of phospholipase C-B mediates Gaq activation. In: Nature Structural and Molecular Biology. 2011 ; Vol. 18, No. 9. pp. 999 - 1006.
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Lyon, AM, Tesmer, VM, Dhamsania, VD, Thal, D, Gutierrez, J, Chowdhury, S, Suddala, KC, Northup, JK & Tesmer, JJG 2011, 'An autoinhibitory helix in the C-terminal region of phospholipase C-B mediates Gaq activation', Nature Structural and Molecular Biology, vol. 18, no. 9, pp. 999 - 1006. https://doi.org/10.1038/nsmb.2095

An autoinhibitory helix in the C-terminal region of phospholipase C-B mediates Gaq activation. / Lyon, Angeline M; Tesmer, Valerie M; Dhamsania, Vishan D; Thal, David; Gutierrez, Joanne; Chowdhury, Shoaib; Suddala, Krishna C; Northup, John K; Tesmer, John Joseph Grubb.

In: Nature Structural and Molecular Biology, Vol. 18, No. 9, 2011, p. 999 - 1006.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Lyon, Angeline M

AU - Tesmer, Valerie M

AU - Dhamsania, Vishan D

AU - Thal, David

AU - Gutierrez, Joanne

AU - Chowdhury, Shoaib

AU - Suddala, Krishna C

AU - Northup, John K

AU - Tesmer, John Joseph Grubb

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AB - The enzyme phospholipase C-? (PLC?) is a crucial regulator of intracellular calcium levels whose activity is controlled by heptahelical receptors that couple to members of the Gq family of heterotrimeric G proteins. We have determined atomic structures of two invertebrate homologs of PLC? (PLC21) from cephalopod retina and identified a helix from the C-terminal regulatory region that interacts with a conserved surface of the catalytic core of the enzyme. Mutations designed to disrupt the analogous interaction in human PLC?3 considerably increase basal activity and diminish stimulation by Gaq. Gaq binding requires displacement of the autoinhibitory helix from the catalytic core, thus providing an allosteric mechanism for activation of PLC?.

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