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Intracellular signaling events are often organized around PDZ (PSD-95lDrosophila Disc large/ZO-1 homology) domain-containing scaffolding proteins. The ubiquitously expressed multi-PDZ protein MUPP1, which is composed of 13 PDZ domains, has been shown to interact with multiple viral and cellular proteins and to play important roles in receptor targeting and trafficking. In this study, we show that MUPP1 binds to the G protein-coupled MT1 melatonin receptor and directly regulates its G1-dependent signal transduction. Structural determinants involved in this interaction are the PDZ10 domain of MUPP1 and the valine of the canonical class III PDZ domain binding motif DSV of the MT1 carboxyl terminus. This high affinity interaction (Kd ∼- 4 nM), which is independent of MT1 activation, occurs in the ovine pars tuberalis of the pituitary expressing both proteins endogenously. Although the disruption of the MT1/MUPP1 interaction has no effect on the subcellular localization, trafficking, or degradation of MT1, it destabilizes the interaction between MT1 and Gi and abolishes Grmediated signaling of MT1. Our findings highlight a previously unappreciated role of PDZ proteins in promoting G protein coupling to receptors. [ABSTRACT FROM AUTHOR]