4BAY

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

Summary for 4BAY

• Entry DOI: 10.2210/pdb4bay/pdb
• Related: 2COM 2H94 2IW5 2UXN 2UXX 2V1D 2X0L 2XAF 2XAG 2XAH 2XAJ 2XAQ 2XAS 2Y48
• Descriptor: LYSINE-SPECIFIC HISTONE DEMETHYLASE 1A, REST COREPRESSOR 1, FLAVIN-ADENINE DINUCLEOTIDE, ... (4 entities in total)
• Functional Keywords: oxidoreductase, demethylase splicing chromatin
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 2
• Total formula weight: 92323.09

Authors

Toffolo, E.,Paganini, L.,Rusconi, F.,Tortorici, M.,Pilotto, S.,Verpelli, C.,Tedeschi, G.,Maffioli, E.,Sala, C.,Mattevi, A.,Battaglioli, E. (deposition date: 2012-09-17, release date: 2013-11-27, Last modification date: 2023-12-20)

Primary citation

Toffolo, E.,Rusconi, F.,Paganini, L.,Tortorici, M.,Pilotto, S.,Heise, C.,Verpelli, C.,Tedeschi, G.,Maffioli, E.,Sala, C.,Mattevi, A.,Battaglioli, E.
Phosphorylation of Neuronal Lysine-Specific Demethylase 1Lsd1/Kdm1A Impairs Transcriptional Repression by Regulating Interaction with Corest and Histone Deacetylases Hdac1/2.
J.Neurochem., 128:616-, 2014

PubMed Abstract: 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.

PubMed: 24111946
DOI: 10.1111/JNC.12457

Experimental method

X-RAY DIFFRACTION (3.1 Å)