PDBsum entry 2x0l

Transcription

PDB id: 2x0l

Contents

Protein chains

670 a.a. *

133 a.a. *

16 a.a. *

Ligands

FAD

* Residue conservation analysis

PDB id:

2x0l

Name:

Transcription

Title:

Crystal structure of a neuro-specific splicing variant of human histone lysine demethylase lsd1.

Structure:

Lysine-specific histone demethylase 1. Chain: a. Synonym: flavin-containing amine oxidase domain-containing protein 2, braf35-hdac complex protein bhc110. Engineered: yes. Rest corepressor 1. Chain: b. Synonym: protein corest, corepressor corest. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Organism_taxid: 9606

Resolution:

3.00Å R-factor: 0.213 R-free: 0.252

Authors:

C.Zibetti,A.Adamo,C.Binda,F.Forneris,C.Verpelli,E.Ginelli,A.Mattevi, C.Sala,E.Battaglioli

Key ref:

C.Zibetti et al. (2010). Alternative splicing of the histone demethylase LSD1/KDM1 contributes to the modulation of neurite morphogenesis in the mammalian nervous system. J Neurosci, 30, 2521-2532. PubMed id: 20164337

Date:

15-Dec-09 Release date: 02-Mar-10

Protein chain

O60341  (KDM1A_HUMAN) -  Lysine-specific histone demethylase 1A from Homo sapiens

Seq: 852 a.a.

Struc: 670 a.a.*

Protein chain

Q9UKL0  (RCOR1_HUMAN) -  REST corepressor 1 from Homo sapiens

Seq: 485 a.a.

Struc: 133 a.a.

Protein chain

P68431  (H31_HUMAN) -  Histone H3.1 from Homo sapiens

Seq: 136 a.a.

Struc: 16 a.a.*

* PDB and UniProt seqs differ at 5 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chain A: E.C.1.14.99.66 - [histone-H3]-N(6),N(6)-dimethyl-L-lysine(4) FAD-dependent demethylase.
• Reaction: N₆,N₆-dimethyl-L-lysyl₄-[histone H3] + 2 A + 2 H2O = L-lysyl₄- [histone H3] + 2 formaldehyde + 2 AH2

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Key reference

J Neurosci 30:2521-2532 (2010)

PubMed id: 20164337

Alternative splicing of the histone demethylase LSD1/KDM1 contributes to the modulation of neurite morphogenesis in the mammalian nervous system.

C.Zibetti, A.Adamo, C.Binda, F.Forneris, E.Toffolo, C.Verpelli, E.Ginelli, A.Mattevi, C.Sala, E.Battaglioli.

ABSTRACT

A variety of chromatin remodeling complexes are thought to orchestrate transcriptional programs that lead neuronal precursors from earliest commitment to terminal differentiation. Here we show that mammalian neurons have a specialized chromatin remodeling enzyme arising from a neurospecific splice variant of LSD1/KDM1, histone lysine specific demethylase 1, whose demethylase activity on Lys4 of histone H3 has been related to gene repression. We found that alternative splicing of LSD1 transcript generates four full-length isoforms from combinatorial retention of two identified exons: the 4 aa exon E8a is internal to the amine oxidase domain, and its inclusion is restricted to the nervous system. Remarkably, the expression of LSD1 splice variants is dynamically regulated throughout cortical development, particularly during perinatal stages, with a progressive increase of LSD1 neurospecific isoforms over the ubiquitous ones. Notably, the same LSD1 splice dynamics can be fairly recapitulated in cultured cortical neurons. Functionally, LSD1 isoforms display in vitro a comparable demethylase activity, yet the inclusion of the sole exon E8a reduces LSD1 repressor activity on a reporter gene. Additional distinction among isoforms is supported by the knockdown of neurospecific variants in cortical neurons resulting in the inhibition of neurite maturation, whereas overexpression of the same variants enhances it. Instead, perturbation of LSD1 isoforms that are devoid of the neurospecific exon elicits no morphogenic effect. Collectively, results demonstrate that the arousal of neuronal LSD1 isoforms pacemakes early neurite morphogenesis, conferring a neurospecific function to LSD1 epigenetic activity.