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Crystal structure of the histone lysine specific demethylase LSD1 complexed with tetrahydrofolate.
Luka Z, Pakhomova S, Loukachevitch LV, Calcutt MW, Newcomer ME, Wagner C
(2014) Protein Sci 23: 993-8
MeSH Terms: Binding Sites, Co-Repressor Proteins, Crystallography, X-Ray, Flavin-Adenine Dinucleotide, Histone Demethylases, Humans, Lysine, Mass Spectrometry, Models, Molecular, Protein Conformation, Substrate Specificity, Tetrahydrofolates
Show Abstract · Added January 20, 2015
An important epigenetic modification is the methylation/demethylation of histone lysine residues. The first histone demethylase to be discovered was a lysine-specific demethylase 1, LSD1, a flavin containing enzyme which carries out the demethylation of di- and monomethyllysine 4 in histone H3. The removed methyl groups are oxidized to formaldehyde. This reaction is similar to those performed by dimethylglycine dehydrogenase and sarcosine dehydrogenase, in which protein-bound tetrahydrofolate (THF) was proposed to serve as an acceptor of the generated formaldehyde. We showed earlier that LSD1 binds THF with high affinity which suggests its possible participation in the histone demethylation reaction. In the cell, LSD1 interacts with co-repressor for repressor element 1 silencing transcription factor (CoREST). In order to elucidate the role of folate in the demethylating reaction we solved the crystal structure of the LSD1-CoREST-THF complex. In the complex, the folate-binding site is located in the active center in close proximity to flavin adenine dinucleotide. This position of the folate suggests that the bound THF accepts the formaldehyde generated in the course of histone demethylation to form 5,10-methylene-THF. We also show the formation of 5,10-methylene-THF during the course of the enzymatic reaction in the presence of THF by mass spectrometry. Production of this form of folate could act to prevent accumulation of potentially toxic formaldehyde in the cell. These studies suggest that folate may play a role in the epigenetic control of gene expression in addition to its traditional role in the transfer of one-carbon units in metabolism.
© 2014 The Protein Society.
0 Communities
1 Members
0 Resources
12 MeSH Terms
XIAP monoubiquitylates Groucho/TLE to promote canonical Wnt signaling.
Hanson AJ, Wallace HA, Freeman TJ, Beauchamp RD, Lee LA, Lee E
(2012) Mol Cell 45: 619-28
MeSH Terms: Animals, Co-Repressor Proteins, Drosophila, Drosophila Proteins, Embryo, Nonmammalian, HEK293 Cells, Humans, Inhibitor of Apoptosis Proteins, Models, Genetic, RNA Interference, Ubiquitination, Wnt Proteins, Wnt Signaling Pathway, Wnt1 Protein, X-Linked Inhibitor of Apoptosis Protein, Xenopus, Xenopus Proteins
Show Abstract · Added June 14, 2013
A key event in Wnt signaling is conversion of TCF/Lef from a transcriptional repressor to an activator, yet how this switch occurs is not well understood. Here, we report an unanticipated role for X-linked inhibitor of apoptosis (XIAP) in regulating this critical Wnt signaling event that is independent of its antiapoptotic function. We identified DIAP1 as a positive regulator of Wingless signaling in a Drosophila S2 cell-based RNAi screen. XIAP, its vertebrate homolog, is similarly required for Wnt signaling in cultured mammalian cells and in Xenopus embryos, indicating evolutionary conservation of function. Upon Wnt pathway activation, XIAP is recruited to TCF/Lef where it monoubiquitylates Groucho (Gro)/TLE. This modification decreases affinity of Gro/TLE for TCF/Lef. Our data reveal a transcriptional switch involving XIAP-mediated ubiquitylation of Gro/TLE that facilitates its removal from TCF/Lef, thus allowing β-catenin-TCF/Lef complex assembly and initiation of a Wnt-specific transcriptional program.
Copyright © 2012 Elsevier Inc. All rights reserved.
2 Communities
4 Members
0 Resources
17 MeSH Terms
Nkx2.2 repressor complex regulates islet β-cell specification and prevents β-to-α-cell reprogramming.
Papizan JB, Singer RA, Tschen SI, Dhawan S, Friel JM, Hipkens SB, Magnuson MA, Bhushan A, Sussel L
(2011) Genes Dev 25: 2291-305
MeSH Terms: Animals, Cell Differentiation, Co-Repressor Proteins, DNA (Cytosine-5-)-Methyltransferases, Diabetes Mellitus, Gene Expression Regulation, Ghrelin, Glucagon, Glucagon-Secreting Cells, Homeodomain Proteins, Insulin, Insulin-Secreting Cells, Mice, Mutation, Organ Specificity, Promoter Regions, Genetic, Protein Binding, Protein Structure, Tertiary, Proteins, Transcription Factors, Zebrafish Proteins
Show Abstract · Added September 3, 2013
Regulation of cell differentiation programs requires complex interactions between transcriptional and epigenetic networks. Elucidating the principal molecular events responsible for the establishment and maintenance of cell fate identities will provide important insights into how cell lineages are specified and maintained and will improve our ability to recapitulate cell differentiation events in vitro. In this study, we demonstrate that Nkx2.2 is part of a large repression complex in pancreatic β cells that includes DNMT3a, Grg3, and HDAC1. Mutation of the endogenous Nkx2.2 tinman (TN) domain in mice abolishes the interaction between Nkx2.2 and Grg3 and disrupts β-cell specification. Furthermore, we demonstrate that Nkx2.2 preferentially recruits Grg3 and HDAC1 to the methylated Aristaless homeobox gene (Arx) promoter in β cells. The Nkx2.2 TN mutation results in ectopic expression of Arx in β cells, causing β-to-α-cell transdifferentiation. A corresponding β-cell-specific deletion of DNMT3a is also sufficient to cause Arx-dependent β-to-α-cell reprogramming. Notably, subsequent removal of Arx in the β cells of Nkx2.2(TNmut/TNmut) mutant mice reverts the β-to-α-cell conversion, indicating that the repressor activities of Nkx2.2 on the methylated Arx promoter in β cells are the primary regulatory events required for maintaining β-cell identity.
3 Communities
2 Members
2 Resources
21 MeSH Terms