Using the yeast two-hybrid system we isolated a cDNA clone encoding a novel protein interacting with the Cterminal domain of the 5-HT Pg receptor. The protein, named MUPP1 (multi-PDZ-domain protein), contains thirteen PDZ domains and no obvious catalytic domain; it is related to hINADL and a putative C. elegans polypeptide referred to as C52A11.4 containing six or ten PDZ domains, respectively. Domains highly similar to those of MUPP1 are arrayed in the same order in all three proteins. The MUPP1 gene is localized on human chromosome 9p24-p22. Transcripts encoding MUPP1 are abundant in the brain as well as in several peripheral organs.z 1998 Federation of European Biochemical Societies.

By using the yeast two-hybrid system, we previously isolated a cDNA clone encoding a novel member of the multivalent PDZ protein family called MUPP1 containing 13 PDZ domains. Here we report that the C terminus of the 5-hydroxytryptamine type 2C (5- There is ample evidence suggesting that the function of a receptor is dependent on its specific subcellular localization. Sequence-specific interactions between proteins provide the basis for the structural and functional organization of receptors within cells. For a few members of the G-protein-coupled receptor family, these interactions have been described to be mediated by C-terminal interactions with PDZ (PSD-95/discs large/ZO-1) domain-containing proteins. The best investigated example is the ␤ 2 -adrenergic receptor, which interacts with the Na ϩ /H ϩ exchanger regulatory factor (NHERF/EBP50) 1 (1). The interaction of NHERF with the ␤ 2 -adrenergic receptor is mediated via binding of the first PDZ domain of NHERF to the extreme C terminus of the ␤ 2 -adrenergic receptor in an agonistdependent manner, thereby regulating Na ϩ /H ϩ exchange (2). NHERF has also been described to link proteins with the actin cytoskeleton through association with ERM (ezrin-radixinmoesin) proteins (3). In fact, the PDZ-mediated interaction of the ␤ 2 -adrenergic receptor with NHERF family proteins has been shown to control recycling of internalized ␤ 2 -adrenergic receptors. Disrupting the ␤ 2 -adrenergic receptor-NHERF interaction perturbs the endocytic sorting of the ␤ 2 -adrenergic receptor, resulting in lysosomal degradation (4).HTC-terminal interactions of G-protein-coupled receptors with PDZ domain-containing proteins extends to a member of the somatostatin receptor family (sst). The subtype sst2 interacts selectively with a highly homologous PDZ domain contained within the protein CortBP1/ProSAP1/Shank2 (5) and the recently cloned synaptic protein SSTRIP (somatostatin receptorinteracting protein)/Spank1/synamon/Shank1 (6). Both proteins belong to a common family recently termed Shanks (7,8) or ProSAP (9), sharing essentially identical domain structures such as ankyrin repeats, an SH3 domain, the PDZ domain, a sterile ␣ motif domain, and a proline-rich region that links Shanks to cortactin, a constituent of the actin cytoskeleton (10).5-HT 2C receptors are broadly expressed in the central nervous system and in the choroid plexus (11,12) and are involved in a diversity of physiological functions such as the control of nociception, motor behavior, endocrine secretion, thermoregulation, modulation of appetite, and the control of exchanges between the central nervous system and the cerebrospinal fluid (13-17). These receptors contain a C-terminal sequence, SSV* (where the asterisk indicates a carboxyl group), corresponding to the T/SXV* motif. This motif is potentially implicated in protein-protein interactions with PDZ domains as originally described for the C termini of the N-methyl-D-aspartate receptor and K ϩ channel subunits (18,19). The T/SXV* motif is also present in C termi...