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4bay

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(New page: '''Unreleased structure''' The entry 4bay is ON HOLD until sometime in the future Authors: Toffolo, E., Paganini, L., Rusconi, F., Tortorici, M., Pilotto, S., Verpelli, C., Tedeschi, G....)
Current revision (11:46, 20 December 2023) (edit) (undo)
 
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'''Unreleased structure'''
 
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The entry 4bay is ON HOLD until sometime in the future
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==Phosphomimetic mutant of LSD1-8a splicing variant in complex with CoREST==
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<StructureSection load='4bay' size='340' side='right'caption='[[4bay]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4bay]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BAY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BAY FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.1&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4bay FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bay OCA], [https://pdbe.org/4bay PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bay RCSB], [https://www.ebi.ac.uk/pdbsum/4bay PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bay ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/KDM1A_HUMAN KDM1A_HUMAN] Histone demethylase that demethylates both 'Lys-4' (H3K4me) and 'Lys-9' (H3K9me) of histone H3, thereby acting as a coactivator or a corepressor, depending on the context. Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed. Acts as a corepressor by mediating demethylation of H3K4me, a specific tag for epigenetic transcriptional activation. Demethylates both mono- (H3K4me1) and di-methylated (H3K4me2) H3K4me. May play a role in the repression of neuronal genes. Alone, it is unable to demethylate H3K4me on nucleosomes and requires the presence of RCOR1/CoREST to achieve such activity. Also acts as a coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and mediating demethylation of H3K9me, a specific tag for epigenetic transcriptional repression. The presence of PRKCB in ANDR-containing complexes, which mediates phosphorylation of 'Thr-6' of histone H3 (H3T6ph), a specific tag that prevents demethylation H3K4me, prevents H3K4me demethylase activity of KDM1A. Demethylates di-methylated 'Lys-370' of p53/TP53 which prevents interaction of p53/TP53 with TP53BP1 and represses p53/TP53-mediated transcriptional activation. Demethylates and stabilizes the DNA methylase DNMT1. Required for gastrulation during embryogenesis. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development.<ref>PMID:12032298</ref> <ref>PMID:15620353</ref> <ref>PMID:16079795</ref> <ref>PMID:17805299</ref> <ref>PMID:20228790</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Epigenetic mechanisms play important roles in brain development, orchestrating proliferation, differentiation, and morphogenesis. Lysine-Specific Demethylase 1 (LSD1 also known as KDM1A and AOF2) is a histone modifier involved in transcriptional repression, forming a stable core complex with the corepressors corepressor of REST (CoREST) and histone deacetylases (HDAC1/2). Importantly, in the mammalian CNS, neuronal LSD1-8a, an alternative splicing isoform of LSD1 including the mini-exon E8a, sets alongside LSD1 and is capable of enhancing neurite growth and morphogenesis. Here, we describe that the morphogenic properties of neuronal LSD1-8a require switching off repressive activity and this negative modulation is mediated in vivo by phosphorylation of the Thr369b residue coded by exon E8a. Three-dimensional crystal structure analysis using a phospho-mimetic mutant (Thr369bAsp), indicate that phosphorylation affects the residues surrounding the exon E8a-coded amino acids, causing a local conformational change. We suggest that phosphorylation, without affecting demethylase activity, causes in neurons CoREST and HDAC1/2 corepressors detachment from LSD1-8a and impairs neuronal LSD1-8a repressive activity. In neurons, Thr369b phosphorylation is required for morphogenic activity, converting neuronal LSD1-8a in a dominant-negative isoform, challenging LSD1-mediated transcriptional repression on target genes.
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Authors: Toffolo, E., Paganini, L., Rusconi, F., Tortorici, M., Pilotto, S., Verpelli, C., Tedeschi, G., Maffioli, E., Sala, C., Mattevi, A., Battaglioli, E.
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Phosphorylation of neuronal Lysine-Specific Demethylase 1LSD1/KDM1A impairs transcriptional repression by regulating interaction with CoREST and histone deacetylases HDAC1/2.,Toffolo E, Rusconi F, Paganini L, Tortorici M, Pilotto S, Heise C, Verpelli C, Tedeschi G, Maffioli E, Sala C, Mattevi A, Battaglioli E J Neurochem. 2013 Sep 20. doi: 10.1111/jnc.12457. PMID:24111946<ref>PMID:24111946</ref>
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Description: Phosphomimetic mutant of LSD1-8a splicing variant in complex with CoREST
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4bay" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Lysine-specific histone demethylase 3D structures|Lysine-specific histone demethylase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Battaglioli E]]
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[[Category: Maffioli E]]
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[[Category: Mattevi A]]
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[[Category: Paganini L]]
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[[Category: Pilotto S]]
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[[Category: Rusconi F]]
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[[Category: Sala C]]
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[[Category: Tedeschi G]]
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[[Category: Toffolo E]]
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[[Category: Tortorici M]]
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[[Category: Verpelli C]]

Current revision

Phosphomimetic mutant of LSD1-8a splicing variant in complex with CoREST

PDB ID 4bay

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