4XBF

Structure of LSD1:CoREST in complex with ssRNA

Summary for 4XBF

• Entry DOI: 10.2210/pdb4xbf/pdb
• Related: 4KUM
• Descriptor: Lysine-specific histone demethylase 1A, REST corepressor 1, RNA (5'-R(*UP*UP*AP*GP*G)-3'), ... (7 entities in total)
• Functional Keywords: lsd1, lysine specific demethylase, demethylase, demethylation, rna, corest, rest co-repressor 1, amine oxidase, coiled-coil, swirm, chromatin remodelling enzyme, epigenetics, histone modifying enzyme, non-coding rna, ncrna, kdm1a, oxidoreductase-transcription-rna complex, oxidoreductase/transcription/rna
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : O60341 Q9UKL0
• Total number of polymer chains: 3
• Total formula weight: 92389.17

Authors

Luka, Z.,Loukachevitch, L.V.,Martin, W.J.,Wagner, C.,Reiter, N.J. (deposition date: 2014-12-16, release date: 2016-04-27, Last modification date: 2023-09-27)

Primary citation

Hirschi, A.,Martin, W.J.,Luka, Z.,Loukachevitch, L.V.,Reiter, N.J.
G-quadruplex RNA binding and recognition by the lysine-specific histone demethylase-1 enzyme.
RNA, 22:1250-1260, 2016

PubMed Abstract: Lysine-specific histone demethylase 1 (LSD1) is an essential epigenetic regulator in metazoans and requires the co-repressor element-1 silencing transcription factor (CoREST) to efficiently catalyze the removal of mono- and dimethyl functional groups from histone 3 at lysine positions 4 and 9 (H3K4/9). LSD1 interacts with over 60 regulatory proteins and also associates with lncRNAs (TERRA, HOTAIR), suggesting a regulatory role for RNA in LSD1 function. We report that a stacked, intramolecular G-quadruplex (GQ) forming TERRA RNA (GG[UUAGGG]8UUA) binds tightly to the functional LSD1-CoREST complex (Kd ≈ 96 nM), in contrast to a single GQ RNA unit ([UUAGGG]4U), a GQ DNA ([TTAGGG]4T), or an unstructured single-stranded RNA. Stabilization of a parallel-stranded GQ RNA structure by monovalent potassium ions (K(+)) is required for high affinity binding to the LSD1-CoREST complex. These data indicate that LSD1 can distinguish between RNA and DNA as well as structured versus unstructured nucleotide motifs. Further, cross-linking mass spectrometry identified the primary location of GQ RNA binding within the SWIRM/amine oxidase domain (AOD) of LSD1. An ssRNA binding region adjacent to this GQ binding site was also identified via X-ray crystallography. This RNA binding interface is consistent with kinetic assays, demonstrating that a GQ-forming RNA can serve as a noncompetitive inhibitor of LSD1-catalyzed demethylation. The identification of a GQ RNA binding site coupled with kinetic data suggests that structured RNAs can function as regulatory molecules in LSD1-mediated mechanisms.

PubMed: 27277658
DOI: 10.1261/rna.057265.116

Experimental method

X-RAY DIFFRACTION (2.803 Å)