title: The PDZ protein mupp1 promotes Gi coupling and signaling of the Mt1 melatonin receptor.
abstract: Intracellular signaling events are often organized around PDZ (PSD-95/Drosophila 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 MT(1) melatonin receptor and directly regulates its G(i)-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 MT(1) carboxyl terminus. This high affinity interaction (K(d) approximately 4 nm), which is independent of MT(1) activation, occurs in the ovine pars tuberalis of the pituitary expressing both proteins endogenously. Although the disruption of the MT(1)/MUPP1 interaction has no effect on the subcellular localization, trafficking, or degradation of MT(1), it destabilizes the interaction between MT(1) and G(i) and abolishes G(i)-mediated signaling of MT(1). Our findings highlight a previously unappreciated role of PDZ proteins in promoting G protein coupling to receptors.
authors: Institut Cochin, Department of Cell Biology, Université Paris Descartes, CNRS (UMR8104), Paris 75014, France.
authors: Jean-Luc
authors: JL
authors: Guillaume
authors: Avais M
authors: AM
authors: Daulat
authors: Pascal
authors: P
authors: Maurice
authors: Angélique
authors: A
authors: Levoye
authors: Martine
authors: M
authors: Migaud
authors: Lena
authors: L
authors: Brydon
authors: Benoît
authors: B
authors: Malpaux
authors: Catherine
authors: C
authors: Borg-Capra
authors: Ralf
authors: R
authors: Jockers
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D008954:Models, Biological; D010902:Pituitary Gland / Q000378:metabolism; D011485:Protein Binding; D044122:Receptor, Melatonin, MT1 / Q000378:metabolism*; D044094:Receptors, Melatonin / Q000378:metabolism; D012756:Sheep; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques; D014633:Valine / Q000737:chemistry
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C491749:Mpdz protein, rat; D044122:Receptor, Melatonin, MT1; D044094:Receptors, Melatonin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D014633:Valine