PNUTS forms a trimeric protein complex with GABAC receptors and protein phosphatase 1

Rose, Mélanie; Dütting, Eva; Schröder, Nadja; Sticht, Heinrich; Brandstätter, Johann Helmut; Enz, Ralf

doi:10.1016/j.mcn.2008.01.004

Cited by 15 publications

(21 citation statements)

References 54 publications

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“…In addition, enzymes such as protein kinase C or protein phosphatase 1 and 2 were repeatedly identified in synaptic preparations, being consistent with the immunohistochemical detection of e.g. protein phosphatase 1 at synaptic sites in the CNS [69][70][71][72]. On the other hand, some mGluR interactors listed in Table 2 were never identified in synaptic protein preparations, possibly caused by their low concentration relative to cytoskeletal proteins or enzymes.…”

Section: )supporting

confidence: 78%

“…Indeed, no PP1γ binding was observed with mGluRs that do not contain the described amino acid sequence [116]. Interestingly, the 5 amino acids fulfill the consensus sequence for a PP1 docking motif that is found in many other regulatory subunits as well, including proteins that link the phosphatase activity to GABAergic signaling [70,118]. The docking motifs present in mGluR C-termini contact a binding pocket on the PP1γ surface in an extended backbone confirmation [69,118].…”

Section: Protein Phosphatasementioning

confidence: 99%

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Metabotropic Glutamate Receptors and Interacting Proteins: Evolving Drug Targets

Enz

2012

CDT

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The correct targeting, localization, regulation and signaling of metabotropic glutamate receptors (mGluRs) represent major mechanisms underlying the complex function of neuronal networks. These tasks are accomplished by the formation of synaptic signal complexes that integrate functionally related proteins such as neurotransmitter receptors, enzymes and scaffold proteins. By these means, proteins interacting with mGluRs are important regulators of glutamatergic neurotransmission. Most described mGluR interaction partners bind to the intracellular C-termini of the receptors. These domains are extensively spliced and phosphorylated, resulting in a high variability of binding surfaces offered to interacting proteins. Malfunction of mGluRs and associated proteins are linked to neurodegenerative and neuropsychiatric disorders including addiction, depression, epilepsy, schizophrenia, Alzheimer's, Huntington's and Parkinson's disease. MGluR associated signal complexes are dynamic structures that assemble and disassemble in response to the neuronal fate. This, in principle, allows therapeutic intervention, defining mGluRs and interacting proteins as promising drug targets. In the last years, several studies elucidated the geometry of mGluRs in contact with regulatory proteins, providing a solid fundament for the development of new therapeutic strategies. Here, I will give an overview of human disorders directly associated with mGluR malfunction, provide an up-to-date summary of mGluR interacting proteins and highlight recently described structures of mGluR domains in contact with binding partners.

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Section: )supporting

confidence: 78%

Section: Protein Phosphatasementioning

confidence: 99%

Metabotropic Glutamate Receptors and Interacting Proteins: Evolving Drug Targets

Enz

2012

CDT

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“…For individual expression of mGluR8a/b, the plasmid amount of 4.1B was substituted by an unrelated expression plasmid encoding for PNUTS (Rose et al 2008) in order to achieve comparable conditions in the transfection/expression procedure. Biotinylation, cell lysis, and purification of biotinylated proteins were performed according to the 'cell-surface protein isolation kit' from Pierce (Pierce Chemical Co., Rockford, IL, USA).…”

Section: Cell Culture Techniquesmentioning

confidence: 99%

Band 4.1 proteins are expressed in the retina and interact with both isoforms of the metabotropic glutamate receptor type 8

Rose

Dütting

Enz

2008

Journal of Neurochemistry

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Abbreviations used: CTD, C-terminal domain; EF1a, elongation factor 1a; GCL, ganglion cell layer; GFP, green fluorescent protein; INL, inner nuclear layer; IPL, inner plexiform layer; MDB, membrane binding domain; mGluR, metabotropic glutamate receptor; ONL, outer nuclear layer; OPL, outer plexiform layer; PICK1, protein interacting with C-kinase; PRS, photoreceptor segments; SAB, spectrin/actin binding domain. AbstractThe function of the CNS depends on the correct regulation of neurotransmitter receptors by interacting proteins. Here, we screened a retinal cDNA library for proteins interacting with the intracellular C-terminus of the metabotropic glutamate receptor isoform 8a (mGluR8a). The band 4.1B protein binds to the C-termini of mGluR8a and mGluR8b, co-localizes with these glutamate receptors in transfected mammalian cells, facilitates their cell surface expression and inhibits the mGluR8 mediated reduction of intracellular cAMP concentrations. In contrast, no interaction with 4.1B was observed for other mGluRs tested. Amino acids encoded by exons 19 and 20 of 4.1B and a stretch of four basic amino acids present in the mGluR8 C-termini mediate the protein interaction. Besides binding to 4.1B, mGluR8 isoforms interact with 4.1G, 4.1N, and 4.1R. Because band 4.1 transcripts undergo extensive alternative splicing, we analyzed the splicing pattern of interacting regions and detected a 4.1B isoform expressed specifically in the retina. Within this tissue, mGluR8 and 4.1B, 4.1G, 4.1N, and 4.1R show a comparable distribution, being expressed in both synaptic layers and in somata of the ganglion cell layer. In summary, our studies identified band 4.1 proteins as new players for the mGluR8 mediated signal transduction.

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“…This sequence (KSV[S/T]W; see Figure 1B) fulfills the consensus sequence of a so-called “PP1 docking motif” that is present in several PP1 interactors, including proteins that target the PP1 activity to ionotropic GABA receptors (Rose et al, 2008). In the literature, various consensus sequences for this docking motif are described, all of them showing different sensitivities and specificities, e.g., (RVxF or [HKR][ACHKMNQRSTV][V][CHKNQRST][FW]; x—any amino acid; Meiselbach et al, 2006; Bollen et al, 2010).…”

Section: Mglur1a Mglur5a/b and Mglur7b In Contact With Protein Phosmentioning

confidence: 97%

Structure of metabotropic glutamate receptor C-terminal domains in contact with interacting proteins

Enz¹

2012

Front. Mol. Neurosci.

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Metabotropic glutamate receptors (mGluRs) regulate intracellular signal pathways that control several physiological tasks, including neuronal excitability, learning, and memory. This is achieved by the formation of synaptic signal complexes, in which mGluRs assemble with functionally related proteins such as enzymes, scaffolds, and cytoskeletal anchor proteins. Thus, mGluR associated proteins actively participate in the regulation of glutamatergic neurotransmission. Importantly, dysfunction of mGluRs and interacting proteins may lead to impaired signal transduction and finally result in neurological disorders, e.g., night blindness, addiction, epilepsy, schizophrenia, autism spectrum disorders and Parkinson's disease. In contrast to solved crystal structures of extracellular N-terminal domains of some mGluR types, only a few studies analyzed the conformation of intracellular receptor domains. Intracellular C-termini of most mGluR types are subject to alternative splicing and can be further modified by phosphorylation and SUMOylation. In this way, diverse interaction sites for intracellular proteins that bind to and regulate the glutamate receptors are generated. Indeed, most of the known mGluR binding partners interact with the receptors' C-terminal domains. Within the last years, different laboratories analyzed the structure of these domains and described the geometry of the contact surface between mGluR C-termini and interacting proteins. Here, I will review recent progress in the structure characterization of mGluR C-termini and provide an up-to-date summary of the geometry of these domains in contact with binding partners.

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PNUTS forms a trimeric protein complex with GABAC receptors and protein phosphatase 1

Cited by 15 publications

References 54 publications

Metabotropic Glutamate Receptors and Interacting Proteins: Evolving Drug Targets

Metabotropic Glutamate Receptors and Interacting Proteins: Evolving Drug Targets

Band 4.1 proteins are expressed in the retina and interact with both isoforms of the metabotropic glutamate receptor type 8

Structure of metabotropic glutamate receptor C-terminal domains in contact with interacting proteins

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