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J. Biol. Chem., Vol. 277, Issue 51, 49707-49715, December 20, 2002

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Role of Dynamic Interactions in Effective Signal Transfer for G Stimulation of Phospholipase C-2^*

Elizabeth Buck^§, Peter Schatz^¶, Suzanne Scarlata, and Ravi Iyengar^**

From the  Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York 10029, ^¶ Affymax Corporation, Palo Alto, California 94304, and the  Department of Physiology, Health Sciences Center, State University of New York, Stonybrook, New York 11729

Heterotrimeric G protein subunits regulate their effectors by protein-protein interactions. The regions involved in these direct interactions have either signal transfer or general binding functions (Buck, E., Li, J., Chen, Y., Weng, G., Scarlata, S., and Iyengar, R. (1999) Science 283, 1332-1335). Although key determinants of signal transfer regions for G protein subunits have been identified, the mechanisms of signal transfer are not fully understood. We have used a combinatorial peptide approach to analyze one G region, G86-105, involved in signal transfer to the effector phospholipase C (PLC)-2 to gain a more mechanistic understanding of G/PLC-2 signaling. Binding and functional studies with the combinatorial peptides on interaction with and stimulation/inhibition of phospholipase C2 indicate that binding affinity can be resolved from EC₅₀ for functional effects, such that peptides that have wild type binding affinities have 15- to 20-fold lower EC₅₀ values. Although more potent, these peptides display a much lower extent of maximal stimulation. These peptides synergize with G or peptides encoding the second G42-54 signal transfer region in maximally stimulating phospholipase C-2. Other combinatorial peptides from the G86-105 region that bind to PLC-2 by themselves submaximally stimulate and extensively inhibit G stimulation of PLC-2. The intrinsic stimulation function can be attributed to Arg-96 and Ser-97, the synergy function to Trp-99, and the binding affinity to Thr-87, Val-90, Pro-94, Arg-96, Ser-97, and Val-100. These results indicate that, even within signal transfer regions, residues involved in binding can be resolved from those involved in signal transfer and that signal transfer is likely to be achieved through dynamic rather than steady-state interactions.

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