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Papers In Press, published online ahead of print February 21, 2003
Department of Pharmacology, Istituto Superiore di Sanità, Rome 00161
Corresponding Author: tomcosta{at}iss.it
Fusion proteins between heptahelical receptors (GPCR) and G protein a-subunits show enhanced signaling efficiency in transfected cells. This is believed the result of molecular proximity, because the interaction between linked modules of one protein chain – if not constrained by structure – should be strongly favored compared to the same in which partners react as free species. To test this assumption we made a series of fusion proteins (type 1 and 4 opioid receptors with Go, and {b}2 adrenergic and dopamine 1 receptors with GsL.) and some mutated analogs carrying different tags and defective GPCR or G{a} units. Using cotransfection experiments with readout protocols able to distinguish activation at fused and non-fused {a}-subunits, we found that both the GPCR and the G{a} limb of one fusion protein can freely interact with non-fused proteins and the tethered partners of a neighboring fusion complex. Moreover, a bulky polyanionic inhibitor can suppress with identical potency receptor-Ga interaction, either when occurring between latched domains of a fused system or separate elements of distinct molecules, indicating that the binding surfaces are equally accessible in both cases. These data demonstrate that there is no entropy drive in the tied condition of fusion proteins, and suggest that their signaling may result from the GPCR of one complex interacting with the a subunit of another. Moreover, the enhanced coupling efficiency commonly observed for fusion proteins is not due to the receptor tether, but to the transmembrane helix, that anchors G{a} to the membrane.
J. Biol. Chem, 10.1074/jbc.M300731200
Submitted on January 22, 2003
Revised on February 12, 2003
Accepted on February 21, 2003
Promiscuous coupling at receptor-G{a} fusion proteins. The receptor of one covalent complex interacts with the {a}-subunit of another
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