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Nils Rademacher, Bettina Schmerl, Jennifer A Lardong, Markus C Wahl, Sarah A Shoichet
At neuronal synapses, multiprotein complexes of trans-synaptic adhesion molecules, scaffold proteins and neurotransmitter receptors assemble to essential building blocks required for synapse formation and maintenance. Here we describe a novel role for the membrane-associated guanylate kinase (MAGUK) protein MPP2 (MAGUK p55 subfamily member 2) at synapses of rat central neurons. Through interactions mediated by its C-terminal SH3-GK domain module, MPP2 binds to the abundant postsynaptic scaffold proteins PSD-95 and GKAP and localises to postsynaptic sites in hippocampal neurons...
October 19, 2016: Scientific Reports
Jinwei Zhu, Yuan Shang, Yitian Xia, Rongguang Zhang, Mingjie Zhang
The membrane-associated guanylate kinase (MAGUK) scaffold proteins share a signature guanylate kinase (GK) domain. Despite their diverse functional roles in cell polarity control and synaptic signaling, the currently known mode of action of MAGUK GK is via its binding to phosphorylated short peptides from target proteins. Here, we discover that the GK domain of DLG MAGUK binds to an unphosphorylated and autonomously folded domain within the stalk region (MAGUK binding stalk [MBS] domain) of a kinesin motor KIF13B with high specificity and affinity...
September 15, 2016: Structure
Erin F Spence, Daniel J Kanak, Benjamin R Carlson, Scott H Soderling
UNLABELLED: Dendritic filopodia are actin-rich structures that are thought to contribute to early spine synapse formation; however, the actin regulatory proteins important for early synaptogenesis are poorly defined. Using organotypic hippocampal slice cultures and primary neuron hippocampal cultures from Arp2/3 conditional knock-out mice, we analyze the roles of the Arp2/3 complex, an actin regulator that creates branched actin networks, and demonstrate it is essential for distinct stages of both structural and functional maturation of excitatory spine synapses...
September 14, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Paul Ugalde-Silva, Octavio Gonzalez-Lugo, Fernando Navarro-Garcia
The intestinal epithelium consists of a single cell layer, which is a critical selectively permeable barrier to both absorb nutrients and avoid the entry of potentially harmful entities, including microorganisms. Epithelial cells are held together by the apical junctional complexes, consisting of adherens junctions, and tight junctions (TJs), and by underlying desmosomes. TJs lay in the apical domain of epithelial cells and are mainly composed by transmembrane proteins such as occludin, claudins, JAMs, and tricellulin, that are associated with the cytoplasmic plaque formed by proteins from the MAGUK family, such as ZO-1/2/3, connecting TJ to the actin cytoskeleton, and cingulin and paracingulin connecting TJ to the microtubule network...
2016: Frontiers in Cellular and Infection Microbiology
César Astorga, Ramón A Jorquera, Mauricio Ramírez, Andrés Kohler, Estefanía López, Ricardo Delgado, Alex Córdova, Patricio Olguín, Jimena Sierralta
The DLG-MAGUK subfamily of proteins plays a role on the recycling and clustering of glutamate receptors (GLUR) at the postsynaptic density. discs-large1 (dlg) is the only DLG-MAGUK gene in Drosophila and originates two main products, DLGA and DLGS97 which differ by the presence of an L27 domain. Combining electrophysiology, immunostaining and genetic manipulation at the pre and postsynaptic compartments we study the DLG contribution to the basal synaptic-function at the Drosophila larval neuromuscular junction...
2016: Scientific Reports
Alejandro Vila, Christopher M Whitaker, John O'Brien
Synaptic processes and plasticity of synapses are mediated by large suites of proteins. In most cases, many of these proteins are tethered together by synaptic scaffold proteins. Scaffold proteins have a large number and typically a variety of protein interaction domains that allow many different proteins to be assembled into functional complexes. As each scaffold protein has a different set of protein interaction domains and a unique set of interacting partners, the presence of synaptic scaffolds can provide insight into the molecular mechanisms that regulate synaptic processes...
August 25, 2016: Journal of Comparative Neurology
Alex Crocker-Buque, Stephen P Currie, Liliana L Luz, Seth G Grant, Kevin R Duffy, Peter C Kind, Michael I Daw
Genetic mutations known to cause intellectual disabilities (ID) are concentrated in specific sets of genes including both those encoding synaptic proteins and those expressed during early development. We have characterised the effect of genetic deletion of Dlg3, an ID-related gene encoding the synaptic NMDA-receptor interacting protein SAP102, on development of the mouse somatosensory cortex. SAP102 is the main representative of the PSD-95 family of postsynaptic MAGUK proteins during early development and is proposed to play a role in stabilising receptors at immature synapses...
July 27, 2016: Human Molecular Genetics
Catherine A Eichel, Adeline Beuriot, Morgan Y E Chevalier, Jean-Sébastien Rougier, Florent Louault, Gilles Dilanian, Julien Amour, Alain Coulombe, Hugues Abriel, Stéphane N Hatem, Elise Balse
RATIONALE: Mechanisms underlying membrane protein localization are crucial in the proper function of cardiac myocytes. The main cardiac sodium channel, NaV1.5, carries the sodium current (INa) that provides a rapid depolarizing current during the upstroke of the action potential. Although enriched in the intercalated disc, NaV1.5 is present in different membrane domains in myocytes and interacts with several partners. OBJECTIVE: To test the hypothesis that the MAGUK (membrane-associated guanylate kinase) protein CASK (calcium/calmodulin-dependent serine protein kinase) interacts with and regulates NaV1...
August 5, 2016: Circulation Research
Jun Luo, Heng Wang, Di Kang, Xuan Guo, Ping Wan, Dou Wang, Jiong Chen
Apical-basal polarity plays critical roles in the functions of epithelial tissues. However, the mechanisms of epithelial polarity establishment and maintenance remain to be fully elucidated. Here we show that the membrane-associated guanylate kinase (MAGUK) family protein Dlg5 is required for the maintenance of apical polarity of follicle epithelium during Drosophila oogenesis. Dlg5 localizes at the apical membrane and adherens junction (AJ) of follicle epithelium in early stage egg chambers. Specifically, we demonstrate that the major function of Dlg5 is to promote apical membrane localization of Crumbs, since overexpression of Crumbs but not other major apical or AJ components could rescue epithelial polarity defects resulted from loss of Dlg5...
2016: Scientific Reports
Svetlana A Ivanova, Anton J M Loonen
A serendipitous pharmacogenetic finding links the vulnerability to developing levodopa-induced dyskinesia to the age of onset of Huntington's disease. Huntington's disease is caused by a polyglutamate expansion of the protein huntingtin. Aberrant huntingtin is less capable of binding to a member of membrane-associated guanylate kinase family (MAGUKs): postsynaptic density- (PSD-) 95. This leaves more PSD-95 available to stabilize NR2B subunit carrying NMDA receptors in the synaptic membrane. This results in increased excitotoxicity for which particularly striatal medium spiny neurons from the indirect extrapyramidal pathway are sensitive...
2016: Parkinson's Disease
Leslie E W LaConte, Vrushali Chavan, Chen Liang, Jeffery Willis, Eva-Maria Schönhense, Susanne Schoch, Konark Mukherjee
CASK, a MAGUK family protein, is an essential protein present in the presynaptic compartment. CASK's cellular role is unknown, but it interacts with multiple proteins important for synapse formation and function, including neurexin, liprin-α, and Mint1. CASK phosphorylates neurexin in a divalent ion-sensitive manner, although the functional relevance of this activity is unclear. Here we find that liprin-α and Mint1 compete for direct binding to CASK, but neurexin1β eliminates this competition, and all four proteins form a complex...
September 2016: Cellular and Molecular Life Sciences: CMLS
Jinwei Zhu, Yuan Shang, Mingjie Zhang
Membrane-associated guanylate kinases (MAGUKs) are a family of scaffold proteins that are highly enriched in synapses and are responsible for organizing the numerous protein complexes required for synaptic development and plasticity. Mutations in genes encoding MAGUKs and their interacting proteins can cause a broad spectrum of human psychiatric disorders. Here, we review MAGUK-mediated synaptic protein complex formation and regulation by focusing on findings from recent biochemical and structural investigations...
April 2016: Nature Reviews. Neuroscience
Gukhan Kim, Rafael Luján, Jochen Schwenk, Melissa H Kelley, Carolina Aguado, Masahiko Watanabe, Bernd Fakler, James Maylie, John P Adelman
Mouse CA1 pyramidal neurons express apamin-sensitive SK2-containing channels in the post-synaptic membrane, positioned close to NMDA-type (N-methyl-D-aspartate) glutamate receptors. Activated by synaptically evoked NMDAR-dependent Ca(2+) influx, the synaptic SK2-containing channels modulate excitatory post-synaptic responses and the induction of synaptic plasticity. In addition, their activity- and protein kinase A-dependent trafficking contributes to expression of long-term potentiation (LTP). We have identified a novel synaptic scaffold, MPP2 (membrane palmitoylated protein 2; p55), a member of the membrane-associated guanylate kinase (MAGUK) family that interacts with SK2-containing channels...
2016: ELife
Jung-Hwa Tao-Cheng, Rita Azzam, Virginia Crocker, Christine A Winters, Tom Reese
Depolarization of neurons in 3-week-old rat hippocampal cultures promotes a rapid increase in the density of surface NMDA receptors (NRs), accompanied by transient formation of nonsynaptic NMDA receptor clusters or NR islands. Islands exhibit cytoplasmic dense material resembling that at postsynaptic densities (PSDs), and contain typical PSD components, including MAGUKS (membrane-associated guanylate kinases), GKAP, Shank, Homer, and CaMKII detected by pre-embedding immunogold electron microscopy. In contrast to mature PSDs, islands contain more NMDA than AMPA receptors, and more SAP102 than PSD-95, features that are shared with nascent PSDs in developing synapses...
November 2015: ENeuro
Xiaobing Chen, Jonathan M Levy, Austin Hou, Christine Winters, Rita Azzam, Alioscka A Sousa, Richard D Leapman, Roger A Nicoll, Thomas S Reese
The postsynaptic density (PSD)-95 family of membrane-associated guanylate kinases (MAGUKs) are major scaffolding proteins at the PSD in glutamatergic excitatory synapses, where they maintain and modulate synaptic strength. How MAGUKs underlie synaptic strength at the molecular level is still not well understood. Here, we explore the structural and functional roles of MAGUKs at hippocampal excitatory synapses by simultaneous knocking down PSD-95, PSD-93, and synapse-associated protein (SAP)102 and combining electrophysiology and transmission electron microscopic (TEM) tomography imaging to analyze the resulting changes...
December 15, 2015: Proceedings of the National Academy of Sciences of the United States of America
Martin Hruska, Nathan T Henderson, Nan L Xia, Sylvain J Le Marchand, Matthew B Dalva
Organization of signaling complexes at excitatory synapses by membrane-associated guanylate kinase (MAGUK) proteins regulates synapse development, plasticity, senescence and disease. Post-translational modification of MAGUK family proteins can drive their membrane localization, yet it is unclear how these intracellular proteins are targeted to sites of synaptic contact. Here we show using super-resolution imaging, biochemical approaches and in vivo models that the trans-synaptic organizing protein ephrin-B3 controls the synaptic localization and stability of PSD-95 and links these events to changes in neuronal activity via negative regulation of a newly identified mitogen-associated protein kinase (MAPK)-dependent phosphorylation site on ephrin-B3, Ser332...
November 2015: Nature Neuroscience
Julia Bender, Maik Engeholm, Marion S Ederer, Johannes Breu, Thor C Møller, Stylianos Michalakis, Tamas Rasko, Erich E Wanker, Martin Biel, Karen L Martinez, Wolfgang Wurst, Jan M Deussing
The corticotropin-releasing hormone receptor type 1 (CRHR1) plays an important role in orchestrating neuroendocrine, behavioral, and autonomic responses to stress. To identify molecules capable of directly modulating CRHR1 signaling, we performed a yeast-two-hybrid screen using the C-terminal intracellular tail of the receptor as bait. We identified several members of the membrane-associated guanylate kinase (MAGUK) family: postsynaptic density protein 95 (PSD95), synapse-associated protein 97 (SAP97), SAP102 and membrane associated guanylate kinase, WW and PDZ domain containing 2 (MAGI2)...
2015: PloS One
Jonathan M Levy, Xiaobing Chen, Thomas S Reese, Roger A Nicoll
The mechanisms controlling synapse growth and maintenance are of critical importance for learning and memory. The MAGUK family of synaptic scaffolding proteins is abundantly expressed at glutamatergic central synapses, but their importance in controlling the synaptic content of glutamate receptors is poorly understood. Here, we use a chained RNAi-mediated knockdown approach to simultaneously remove PSD-93, PSD-95, and SAP102, the MAGUKs previously shown to be responsible for synaptic localization of glutamate receptors...
August 5, 2015: Neuron
Marcin A Listowski, Jacek Leluk, Sebastian Kraszewski, Aleksander F Sikorski
Cholesterol is essential for the proper organization of the biological membrane. Therefore, predicting which proteins can bind cholesterol is important in understanding how proteins participate in lateral membrane organization. In this study, a simple bioinformatics approach was used to establish whether MPP1, a member of the MAGUK protein family, is capable of binding cholesterol. Modelled and experimentally-validated fragment structures were mined from online resources and searched for CRAC and CRAC-like motifs...
2015: PloS One
Yaqing Wang, Li Yuan
Calcium/calmodulin dependent serine protein kinase (CASK), which belongs to the family of membrane associated guanylate kinase (MAGUK) proteins, has several isoforms. CASK expresses differently in embryonic tissues and adult tissues. It can be modulated by phosphorylation and SUMOylation. CASK plays an important role in neural development, spermatozoal development and renal development. Dysfunction of CASK may lead to diseases. CASK is distributed extensively in the brain, regulating synapse formation. Mutation of CASK can lead to several neurologic diseases...
June 2015: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
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