4gur

Crystal structure of LSD2-NPAC with H3 in space group P21Crystal structure of LSD2-NPAC with H3 in space group P21

Structural highlights

4gur is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	4gu1, 4gus, 4gut
Gene:	LSD2 (Homo sapiens), GLYR1 (Homo sapiens)
Resources:	FirstGlance, OCA, RCSB, PDBsum

Function

[GLYR1_HUMAN] May have oxidoreductase activity. Regulates p38 MAP kinase activity by mediating stress activation of p38alpha/MAPK14 and specifically regulating MAPK14 signaling. Indirectly promotes phosphorylation of MAPK14 and activation of ATF2. The phosphorylation of MAPK14 requires upstream activity of MAP2K4 and MAP2K6. Recruited on chromatin, recognizes and binds trimethylated 'Lys-36' of histone H3 (H3K36me3).^[1] ^[2]

Publication Abstract from PubMed

Dynamic regulation of histone methylation represents a fundamental epigenetic mechanism underlying eukaryotic gene regulation, yet little is known about how the catalytic activities of histone demethylases are regulated. Here, we identify and characterize NPAC/GLYR1 as an LSD2/KDM1b-specific cofactor that stimulates H3K4me1 and H3K4me2 demethylation. We determine the crystal structures of LSD2 alone and LSD2 in complex with the NPAC linker region in the absence or presence of histone H3 peptide, at resolutions of 2.9, 2.0, and 2.25 A, respectively. These crystal structures and further biochemical characterization define a dodecapeptide of NPAC (residues 214-225) as the minimal functional unit for its cofactor activity and provide structural determinants and a molecular mechanism underlying the intrinsic cofactor activity of NPAC in stimulating LSD2-catalyzed H3K4 demethylation. Thus, these findings establish a model for how a cofactor directly regulates histone demethylation and will have a significant impact on our understanding of catalytic-activity-based epigenetic regulation.

LSD2/KDM1B and Its Cofactor NPAC/GLYR1 Endow a Structural and Molecular Model for Regulation of H3K4 Demethylation.,Fang R, Chen F, Dong Z, Hu D, Barbera AJ, Clark EA, Fang J, Yang Y, Mei P, Rutenberg M, Li Z, Zhang Y, Xu Y, Yang H, Wang P, Simon MD, Zhou Q, Li J, Marynick MP, Li X, Lu H, Kaiser UB, Kingston RE, Xu Y, Shi YG Mol Cell. 2012 Dec 19. pii: S1097-2765(12)00976-8. doi:, 10.1016/j.molcel.2012.11.019. PMID:23260659^[3]

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

References

↑ Fu J, Yang Z, Wei J, Han J, Gu J. Nuclear protein NP60 regulates p38 MAPK activity. J Cell Sci. 2006 Jan 1;119(Pt 1):115-23. Epub 2005 Dec 13. PMID:16352664 doi:10.1242/jcs.02699
↑ Vermeulen M, Eberl HC, Matarese F, Marks H, Denissov S, Butter F, Lee KK, Olsen JV, Hyman AA, Stunnenberg HG, Mann M. Quantitative interaction proteomics and genome-wide profiling of epigenetic histone marks and their readers. Cell. 2010 Sep 17;142(6):967-80. doi: 10.1016/j.cell.2010.08.020. PMID:20850016 doi:10.1016/j.cell.2010.08.020
↑ Fang R, Chen F, Dong Z, Hu D, Barbera AJ, Clark EA, Fang J, Yang Y, Mei P, Rutenberg M, Li Z, Zhang Y, Xu Y, Yang H, Wang P, Simon MD, Zhou Q, Li J, Marynick MP, Li X, Lu H, Kaiser UB, Kingston RE, Xu Y, Shi YG. LSD2/KDM1B and Its Cofactor NPAC/GLYR1 Endow a Structural and Molecular Model for Regulation of H3K4 Demethylation. Mol Cell. 2012 Dec 19. pii: S1097-2765(12)00976-8. doi:, 10.1016/j.molcel.2012.11.019. PMID:23260659 doi:10.1016/j.molcel.2012.11.019

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OCA

[1] Fu J, Yang Z, Wei J, Han J, Gu J. Nuclear protein NP60 regulates p38 MAPK activity. J Cell Sci. 2006 Jan 1;119(Pt 1):115-23. Epub 2005 Dec 13. PMID:16352664 doi:10.1242/jcs.02699

[2] Vermeulen M, Eberl HC, Matarese F, Marks H, Denissov S, Butter F, Lee KK, Olsen JV, Hyman AA, Stunnenberg HG, Mann M. Quantitative interaction proteomics and genome-wide profiling of epigenetic histone marks and their readers. Cell. 2010 Sep 17;142(6):967-80. doi: 10.1016/j.cell.2010.08.020. PMID:20850016 doi:10.1016/j.cell.2010.08.020

[3] Fang R, Chen F, Dong Z, Hu D, Barbera AJ, Clark EA, Fang J, Yang Y, Mei P, Rutenberg M, Li Z, Zhang Y, Xu Y, Yang H, Wang P, Simon MD, Zhou Q, Li J, Marynick MP, Li X, Lu H, Kaiser UB, Kingston RE, Xu Y, Shi YG. LSD2/KDM1B and Its Cofactor NPAC/GLYR1 Endow a Structural and Molecular Model for Regulation of H3K4 Demethylation. Mol Cell. 2012 Dec 19. pii: S1097-2765(12)00976-8. doi:, 10.1016/j.molcel.2012.11.019. PMID:23260659 doi:10.1016/j.molcel.2012.11.019

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