MPP2 is a postsynaptic MAGUK scaffold protein that links SynCAM1 cell adhesion molecules to core components of the postsynaptic density

Rademacher, Nils; Schmerl, Bettina; Lardong, J.A.; Wahl, Markus C.; Shoichet, Sarah A.

doi:10.1038/srep35283

Cited by 27 publications

(29 citation statements)

References 41 publications

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“…Mixed cultures of primary hippocampal neurons were generated as reported earlier (Rademacher et al, 2016). Briefly, E18 Wistar pups were decapitated, and hippocampi were isolated and collected in ice-cold DMEM (Lonza).…”

Section: Methodsmentioning

confidence: 99%

Intramolecular domain dynamics regulate synaptic MAGUK protein interactions

Rademacher

Kuropka

Kunde

et al. 2019

eLife

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PSD-95 MAGUK family scaffold proteins are multi-domain organisers of synaptic transmission that contain three PDZ domains followed by an SH3-GK domain tandem. This domain architecture allows coordinated assembly of protein complexes composed of neurotransmitter receptors, synaptic adhesion molecules and downstream signalling effectors. Here we show that binding of monomeric CRIPT-derived PDZ3 ligands to the third PDZ domain of PSD-95 induces functional changes in the intramolecular SH3-GK domain assembly that influence subsequent homotypic and heterotypic complex formation. We identify PSD-95 interactors that differentially bind to the SH3-GK domain tandem depending on its conformational state. Among these interactors, we further establish the heterotrimeric G protein subunit Gnb5 as a PSD-95 complex partner at dendritic spines of rat hippocampal neurons. The PSD-95 GK domain binds to Gnb5, and this interaction is triggered by CRIPT-derived PDZ3 ligands binding to the third PDZ domain of PSD-95, unraveling a hierarchical binding mechanism of PSD-95 complex formation.

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Section: Methodsmentioning

confidence: 99%

Intramolecular domain dynamics regulate synaptic MAGUK protein interactions

Rademacher

Kuropka

Kunde

et al. 2019

eLife

Self Cite

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“…MPP2 is localized at the postsynapse and interacts with many PSD proteins, including itself, PSD95, SAP97, and actin, but also CaMKIIα, suggesting a role as a scaffold protein [248]. Recently, MPP2 was found to interact also with guanylate kinase-associated protein (GKAP) and the synaptic cell adhesion molecule (SynCAM1) 1, a protein also involved in structuring PSDs [249]. MPP2 also interacts with small conductance-activated potassium SK2 channels and positions them properly at the synapse, a crucial element for their role in synaptic plasticity [250].…”

Section: Pdz Domain-containing Interactantsmentioning

confidence: 99%

AMPA receptors and their minions: auxiliary proteins in AMPA receptor trafficking

Bissen

Foss

Acker‐Palmer

2019

Cell. Mol. Life Sci.

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To correctly transfer information, neuronal networks need to continuously adjust their synaptic strength to extrinsic stimuli. This ability, termed synaptic plasticity, is at the heart of their function and is, thus, tightly regulated. In glutamatergic neurons, synaptic strength is controlled by the number and function of AMPA receptors at the postsynapse, which mediate most of the fast excitatory transmission in the central nervous system. Their trafficking to, at, and from the synapse, is, therefore, a key mechanism underlying synaptic plasticity. Intensive research over the last 20 years has revealed the increasing importance of interacting proteins, which accompany AMPA receptors throughout their lifetime and help to refine the temporal and spatial modulation of their trafficking and function. In this review, we discuss the current knowledge about the roles of key partners in regulating AMPA receptor trafficking and focus especially on the movement between the intracellular, extrasynaptic, and synaptic pools. We examine their involvement not only in basal synaptic function, but also in Hebbian and homeostatic plasticity. Included in our review are well-established AMPA receptor interactants such as GRIP1 and PICK1, the classical auxiliary subunits TARP and CNIH, and the newest additions to AMPA receptor native complexes.

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“…In depth analysis of the genes that underwent RNA editing identified several interesting facts. Two genes, MLLT6 and MPP2, that were most edited in control brain compared to GBM have been implicated in leukemogenesis and cell adhesion/cytoskeleton regulatory functions (Rademacher et al, 2016;Saha et al, 1995). We also carried out Gene Ontology (GO) analysis to find pathways that get regulated by editing to understand further the role of RNA editing in gliomagenesis.…”

Section: Pathway Analysis Of Genes Exhibiting Differential Rna Editinmentioning

confidence: 99%

Global RNA editome landscape discovers reduced RNA editing in glioma: loss of editing of gamma-amino butyric acid receptor alpha subunit 3 (GABRA3) favors glioma migration and invasion

Patil

Pal

Mahalingam

et al. 2020

PeerJ

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Background Gliomas are the most common and lethal type of intracranial tumors. With the current treatment regime, the median survival of patients with grade IV glioma (glioblastoma/GBM) remains at 14–16 months. RNA editing modifies the function and regulation of transcripts. The development of glial tumors may be caused by altered RNA editing events. Methods In this study, we uncover the global RNA editome landscape of glioma patients from RNA-seq data of control, lower grade glioma (LGG) and GBM samples (n = 1,083). Results A-to-I editing events were found to comprise 80% of the total editing events of which 96% were located in the Alu regions. The total RNA editing events were found to be reduced in glioma compared to control samples. More specifically, we found Gamma-aminobutyric acid type A receptor alpha3 (GABRA3) to be edited (c.1026 A-to-G; pI343M) in 73% (editing ratio 0.8) of control samples compared to LGG (28.96%; 0.47) and GBM (5.2%; 0.53) samples. GABRA3 transcript level was found to be downregulated in glioma compared to control in a grade-specific manner with GBMs having the lowest level of the transcript. Further, GABRA3 transcripts were observed to be higher in edited compared to unedited glioma samples. The transcript and protein levels of exogenously expressed gene were found to be higher for edited compared to unedited GABRA3 in glioma cells. Further, exogenously expressed edited GABRA3 inhibited migration and invasion of glioma cells efficiently but not the unedited GABRA3. Conclusion Collectively, our study discovered a reduction in RNA editing during glioma development. We further demonstrate that elevated RNA editing maintains a high level of GABRA3 RNA and protein in normal glial cells which provides a less migratory environment for the normal functioning of the brain. In contrast, the reduction in GABRA3 protein levels, due to lower stability of unedited RNA, results in the loss of function which confers an aggressive phenotype to GBM tumor.

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MPP2 is a postsynaptic MAGUK scaffold protein that links SynCAM1 cell adhesion molecules to core components of the postsynaptic density

Cited by 27 publications

References 41 publications

Intramolecular domain dynamics regulate synaptic MAGUK protein interactions

Intramolecular domain dynamics regulate synaptic MAGUK protein interactions

AMPA receptors and their minions: auxiliary proteins in AMPA receptor trafficking

Global RNA editome landscape discovers reduced RNA editing in glioma: loss of editing of gamma-amino butyric acid receptor alpha subunit 3 (GABRA3) favors glioma migration and invasion

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