4czz

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Histone demethylase LSD1(KDM1A)-CoREST3 Complex

Structural highlights

4czz is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3Å
Ligands:FAD
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

KDM1A_HUMAN Histone demethylase that demethylates both 'Lys-4' (H3K4me) and 'Lys-9' (H3K9me) of histone H3, thereby acting as a coactivator or a corepressor, depending on the context. Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed. Acts as a corepressor by mediating demethylation of H3K4me, a specific tag for epigenetic transcriptional activation. Demethylates both mono- (H3K4me1) and di-methylated (H3K4me2) H3K4me. May play a role in the repression of neuronal genes. Alone, it is unable to demethylate H3K4me on nucleosomes and requires the presence of RCOR1/CoREST to achieve such activity. Also acts as a coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and mediating demethylation of H3K9me, a specific tag for epigenetic transcriptional repression. The presence of PRKCB in ANDR-containing complexes, which mediates phosphorylation of 'Thr-6' of histone H3 (H3T6ph), a specific tag that prevents demethylation H3K4me, prevents H3K4me demethylase activity of KDM1A. Demethylates di-methylated 'Lys-370' of p53/TP53 which prevents interaction of p53/TP53 with TP53BP1 and represses p53/TP53-mediated transcriptional activation. Demethylates and stabilizes the DNA methylase DNMT1. Required for gastrulation during embryogenesis. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development.[1] [2] [3] [4] [5]

Publication Abstract from PubMed

Mammalian genomes harbor three CoREST genes. rcor1 encodes CoREST (CoREST1) and the paralogues rcor2 and rcor3 encode CoREST2 and CoREST3, respectively. Here, we describe specific properties of transcriptional complexes formed by CoREST proteins with the histone demethylase LSD1/KDM1A and histone deacetylases HDAC1/2 and the finding that all three CoRESTs express in the adult rat brain. CoRESTs interact equally strong with LSD1/KDM1A. Structural analysis shows that the overall conformation of CoREST3 is similar to that of CoREST1 complexed with LSD1/KDM1A. Nonetheless, transcriptional repressive capacity of CoREST3 is lower than that of CoREST1, which correlates with the observation that CoREST3 leads to a reduced LSD1/KDM1A catalytic efficiency. Also, CoREST2 shows a lower transcriptional repression than CoREST1, which is resistant to HDAC inhibitors. CoREST2 displays lower interaction with HDAC1/2 which is barely present in LSD1/KDM1A-CoREST2 complexes. A non-conserved Leucine in the first SANT domain of CoREST2 severely weakens its association to HDAC1/2. Furthermore, CoREST2 mutants with either increased or lacking HDAC1/2 interaction feature equivalent transcriptional repression capacities, indicating that CoREST2 represses in a HDAC-independent manner. In conclusion, differences among CoREST proteins are instrumental to the modulation of protein-protein interactions and catalytic activities of LSD1/KDM1A-CoREST-HDAC complexes, fine tuning gene expression regulation.

Differential properties of transcriptional complexes formed by the CoREST family.,Barrios AP, Gomez AV, Saez JE, Ciossani G, Toffolo E, Battaglioli E, Mattevi A, Andres ME Mol Cell Biol. 2014 May 12. PMID:24820421[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Hakimi MA, Bochar DA, Chenoweth J, Lane WS, Mandel G, Shiekhattar R. A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes. Proc Natl Acad Sci U S A. 2002 May 28;99(11):7420-5. PMID:12032298 doi:10.1073/pnas.112008599
  2. ↑ Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 2004 Dec 29;119(7):941-53. PMID:15620353 doi:http://dx.doi.org/10.1016/j.cell.2004.12.012
  3. ↑ Metzger E, Wissmann M, Yin N, Muller JM, Schneider R, Peters AH, Gunther T, Buettner R, Schule R. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature. 2005 Sep 15;437(7057):436-9. Epub 2005 Aug 3. PMID:16079795 doi:http://dx.doi.org/10.1038/nature04020
  4. ↑ Huang J, Sengupta R, Espejo AB, Lee MG, Dorsey JA, Richter M, Opravil S, Shiekhattar R, Bedford MT, Jenuwein T, Berger SL. p53 is regulated by the lysine demethylase LSD1. Nature. 2007 Sep 6;449(7158):105-8. PMID:17805299 doi:nature06092
  5. ↑ Metzger E, Imhof A, Patel D, Kahl P, Hoffmeyer K, Friedrichs N, Muller JM, Greschik H, Kirfel J, Ji S, Kunowska N, Beisenherz-Huss C, Gunther T, Buettner R, Schule R. Phosphorylation of histone H3T6 by PKCbeta(I) controls demethylation at histone H3K4. Nature. 2010 Apr 1;464(7289):792-6. doi: 10.1038/nature08839. Epub 2010 Mar 14. PMID:20228790 doi:http://dx.doi.org/10.1038/nature08839
  6. ↑ Barrios AP, Gomez AV, Saez JE, Ciossani G, Toffolo E, Battaglioli E, Mattevi A, Andres ME. Differential properties of transcriptional complexes formed by the CoREST family. Mol Cell Biol. 2014 May 12. PMID:24820421 doi:http://dx.doi.org/10.1128/MCB.00083-14

Contents


PDB ID 4czz

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