 |
PDBsum entry 4xbf
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Oxidoreductase/transcription/RNA
|
PDB id
|
|
|
|
4xbf
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
G-Quadruplex RNA binding and recognition by the lysine-Specific histone demethylase-1 enzyme.
|
|
|
Authors
|
|
A.Hirschi,
W.J.Martin,
Z.Luka,
L.V.Loukachevitch,
N.J.Reiter.
|
|
|
Ref.
|
|
Rna, 2016,
22,
1250-1260.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
