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1.
Neuron ; 86(2): 475-89, 2015 Apr 22.
Article in English | MEDLINE | ID: mdl-25843401

ABSTRACT

PSD-95 is a prominent organizer of the postsynaptic density (PSD) that can present a filamentous orientation perpendicular to the plasma membrane. Interactions between PSD-95 and transmembrane proteins might be particularly sensitive to this orientation, as "long" cytoplasmic tails might be required to reach deeper PSD-95 domains. Extension/retraction of transmembrane protein C-tails offer a new way of regulating binding to PSD-95. Using stargazin as a model, we found that enhancing the apparent length of stargazin C-tail through phosphorylation or by an artificial linker was sufficient to potentiate binding to PSD-95, AMPAR anchoring, and synaptic transmission. A linear extension of stargazin C-tail facilitates binding to PSD-95 by preferentially engaging interaction with the farthest located PDZ domains regarding to the plasma membrane, which present a greater affinity for the stargazin PDZ-domain-binding motif. Our study reveals that the concerted orientation of the stargazin C-tail and PSD-95 is a major determinant of synaptic strength.


Subject(s)
Calcium Channels/chemistry , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/metabolism , Neurons/metabolism , Receptors, AMPA/metabolism , Synaptic Transmission/physiology , Amino Acid Motifs , Animals , COS Cells , Chlorocebus aethiops , Disks Large Homolog 4 Protein , Hippocampus/cytology , Phosphorylation , Rats
2.
Mol Endocrinol ; 28(2): 183-96, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24422630

ABSTRACT

Estrogen receptors (ERs) are ligand-activated transcription factors involved in many physiological and pathological processes, including breast cancer. Their activity is fine-tuned by posttranslational modifications, notably sumoylation. In the present study, we investigated the role of the small ubiquitin-related modifier (SUMO) protease, SUMO1/sentrin/suppressor of Mif 2-specific peptidase 2 (SENP2), in the regulation of ERα activity. We first found SENP2 to significantly repress estradiol-induced transcriptional activity in breast cancer cells (MCF7 and T47D). This effect was observed with a reporter plasmid and on endogenous genes such as TFF1 and CTSD, which were shown to recruit SENP2 in chromatin immunoprecipitation experiments. Using glutathione S-transferase pull-down, coimmunoprecipitation and proximity ligation assays, SENP2 was found to interact with ERα and this interaction to be mediated by the amino-terminal region of the protease and the hinge region of the receptor. Interestingly, we demonstrated that ERα repression by SENP2 is independent of its SUMO protease activity and requires a transcriptional repressive domain located in the amino-terminal end of the protease. Using small interfering RNA assays, we evidenced that this domain recruits the histone deacetylase 3 (HDAC3), to be fully active. Furthermore, using both overexpression and knockdown strategies, we showed that SENP2 robustly represses estrogen-dependent and independent proliferation of MCF7 cells. We provided evidence that this effect requires both the proteolytic and transcriptional activities of SENP2. Altogether, our study unravels a new property for a SUMO protease and identifies SENP2 as a classical transcription coregulator.


Subject(s)
Cysteine Endopeptidases/physiology , Estrogen Receptor alpha/physiology , Gene Expression Regulation, Neoplastic , Gene Silencing , Breast Neoplasms , Cell Proliferation , Estradiol/physiology , Female , Histone Deacetylases/metabolism , Humans , MCF-7 Cells , Promoter Regions, Genetic , Protein Binding , Protein Structure, Tertiary , Transcription, Genetic
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