click to enlarge
Gary Waldo, Research Analyst in the Harden Lab and first author on paper published today in Science
Two Labs in the Department of Pharmacology, published a paper today in the journal Science within the Science Express website (October 21, 2010) that details the exact atomic structure and mechanisms of a major cellular signaling pathway. G-Protein-coupled receptors, which live in the outer membranes of cells take signals from outside the cell and convert them into responses inside the cells, responses controling behaviors such as cell growth, muscle contraction, sight, smell, and platelet aggregation.
While it has been known that G-protein-coupled receptors work with the G-protein, Gq and an enzyme called phospholipase C (PLC) to do this, up to now it has remained a mystery as to how this occurs. To understand how PLC binds with Gq, Gary Waldo, first author on the paper, used robotics to create and capture images of crystallized g-protein, then shifted through thousands of images until he finally found one that showed PLC bound to Gq.
Once the structure was figured out, they were able to alter different parts of the protein to get a better understanding of how PLC and Gq interact to turn a signal on and off. This knowledge will also lead to a better understanding of how the complex regulates cell processes, such as cell proliferation and how mutations in these cells contribute to diseases such as cancer.
Along with Ken Harden, PhD, John Sondek, PhD, and Gary Waldo, PhD, other UNC co-authors on the paper include Tiffany Ricks, PhD; Stephanie Hicks, PhD; and Matthew Cheever, PhD. Additional co-authors were Takeharu Kawano and Kazuhito Tsuboi, University of Illinois; Xiaoyue Wang and Craig Montell , Johns Hopkins University; and Tohru Kozasa, University of Tokyo.
Above: Active site: Molecular representation of the
active site of Gq stabilized by PLC. Click image for enlargement.
Above: Overall structure: The switch regions (red) toggle Gq
“on” and “off”. Here PLC (yellow) is shown bound to a space-filling
representation of active Gq. Click image for enlargement.
Read more in UNC Medical Center News
Read the abstract in Science Express online
Published Nov. 12, 2010 Citation: Waldo, G.L., Ricks, T.K., Hicks, S.N., Cheever, M.L., Kawano, T., Tzuboi, K., Wang, X., Montell, C., Kozasa, T., Sondek, J. and Harden, T.K. (2010) Kinetic Scaffolding Mediated by a Phospholipase C-β and Gq Signaling Complex. Science 330: 974-980.