An autoinhibitory helix in the C-terminal region of phospholipase C-β mediates Gα q activation

• Published in: Nature structural & molecular biology Vol. 18; no. 9; pp. 999 - 1005
• Main Authors: Northup, John K, Tesmer, John J G, Lyon, Angeline M, Tesmer, Valerie M, Dhamsania, Vishan D, Thal, David M, Gutierrez, Joanne, Chowdhury, Shoaib, Suddala, Krishna C
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 07.08.2011
• Subjects: 631/45/535; 631/80/86; Animals; Biochemistry; Biological Microscopy; Biomedical and Life Sciences; Crystallography, X-Ray; GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism; Life Sciences; Loligo - enzymology; Membrane Biology; Models, Molecular; Mutagenesis, Site-Directed; Phospholipase C beta - chemistry; Phospholipase C beta - physiology; Protein Structure; Protein Structure, Secondary - physiology; Protein Structure, Tertiary; Sepia - enzymology
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/nsmb.2095

By examining the structure of phospholipase C-β, an autoinhibitory helix that interacts with the catalytic core of this enzyme is now identified. Disrupting this interaction enhances basal activity and decreases stimulation by Gα q , supporting an allosteric mechanism for PLCβ activation through displacement of the autoinhibitory helix by Gαq. The enzyme phospholipase C-β (PLCβ) is a crucial regulator of intracellular calcium levels whose activity is controlled by heptahelical receptors that couple to members of the G q family of heterotrimeric G proteins. We have determined atomic structures of two invertebrate homologs of PLCβ (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 PLCβ3 considerably increase basal activity and diminish stimulation by Gα q . Gα q binding requires displacement of the autoinhibitory helix from the catalytic core, thus providing an allosteric mechanism for activation of PLCβ.