The PDZ protein mupp1 promotes Gi coupling and signaling of the Mt1 melatonin receptor.
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.
Guillaume
Jean-Luc
JL
Institut Cochin, Department of Cell Biology, Université Paris Descartes, CNRS (UMR8104), Paris 75014, France.
Daulat
Avais M
AM
Maurice
Pascal
P
Levoye
Angélique
A
Migaud
Martine
M
Brydon
Lena
L
Malpaux
Benoît
B
Borg-Capra
Catherine
C
Jockers
Ralf
R
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
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