Lysine-specific histone demethylase

From Proteopedia

Human FAD-containing LSD1 (cyan) complex with CoREST (green) and histone H3 helix (deeppink), 2v1d

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1 Function
2 Relevance
3 Structural highlights
4 3D structures of lysine-specific histone demethylase

Function

Lysine-specific histone demethylase 1 or 1A (LSD1) is a flavin-dependent oxidase that catalyzes the removal of methyl groups from mono- and dimethylated lysine 4 of histone H3. LSD1 is a nuclear homolog of amine oxidase. LSD contains a SWIRM domain which is a small a-helical domain which binds DNA. It functions as histone demethylase and transcriptional corepressor. LSD1 demethylation occurs via a reaction which produces formaldehyde. LSD1 is a component of transcriptional co-repressor complex which also contains CoREST (co-repressor of element-1-silencing transcription factor)^[1].
See also Lysine-specific demethylase 1 (LSD-1).

Lysine-specific histone demethylase 2 or 1B (LSD2) is a flavin-dependent oxidase that catalyzes the removal of methyl groups from mono- and dimethylated lysine 9 of histone H3.
Lysine-specific histone demethylase 5A or KDM5A is essential for the repression of astrocyte differentiation^[2].
Lysine-specific histone demethylase 5B or KDM5B or retinoblastoma-binding protein Rbbp2 homolog (LSD5B) is a JmjC domain containing histone demethylase and is an improtant component of DNA repair

Relevance

LSD1 is a potential anti-tumor drug target since it inhibits the tumor suppressor p53^[3]. LSD2 demethylation activity helps in increased binding of NF-kB and activation of several inflammatory genes^[4]. LSD5B deficiency promotes DNA damage processes^[5].

Structural highlights

. : a flexible N-terminal domain, a SWIRM domain (an α-helical domain found in chromosomal proteins mediating protein-protein interactions in chromatin), a substrate and FAD-binding domain, a tower domain (a pair of 2 long anti-parallel helices supporting a 3-helix bundle) and a C-terminal domain^[6]. .

3D structures of lysine-specific histone demethylase

Lysine-specific histone demethylase 3D structures

References

↑ Chen Y, Jie W, Yan W, Zhou K, Xiao Y. Lysine-specific histone demethylase 1 (LSD1): A potential molecular target for tumor therapy. Crit Rev Eukaryot Gene Expr. 2012;22(1):53-9. PMID:22339659
↑ Kong SY, Kim W, Lee HR, Kim HJ. The histone demethylase KDM5A is required for the repression of astrocytogenesis and regulated by the translational machinery in neural progenitor cells. FASEB J. 2018 Feb;32(2):1108-1119. doi: 10.1096/fj.201700780R. Epub 2018 Jan 3. PMID:29212818 doi:http://dx.doi.org/10.1096/fj.201700780R
↑ Pollock JA, Larrea MD, Jasper JS, McDonnell DP, McCafferty DG. Lysine-specific histone demethylase 1 inhibitors control breast cancer proliferation in ERalpha-dependent and -independent manners. ACS Chem Biol. 2012 Jul 20;7(7):1221-31. doi: 10.1021/cb300108c. Epub 2012 May, 10. PMID:22533360 doi:http://dx.doi.org/10.1021/cb300108c
↑ van Essen D, Zhu Y, Saccani S. A feed-forward circuit controlling inducible NF-kappaB target gene activation by promoter histone demethylation. Mol Cell. 2010 Sep 10;39(5):750-60. doi: 10.1016/j.molcel.2010.08.010. PMID:20832726 doi:http://dx.doi.org/10.1016/j.molcel.2010.08.010
↑ Li X, Liu L, Yang S, Song N, Zhou X, Gao J, Yu N, Shan L, Wang Q, Liang J, Xuan C, Wang Y, Shang Y, Shi L. Histone demethylase KDM5B is a key regulator of genome stability. Proc Natl Acad Sci U S A. 2014 May 13;111(19):7096-101. doi:, 10.1073/pnas.1324036111. Epub 2014 Apr 28. PMID:24778210 doi:http://dx.doi.org/10.1073/pnas.1324036111
↑ Chen Y, Yang Y, Wang F, Wan K, Yamane K, Zhang Y, Lei M. Crystal structure of human histone lysine-specific demethylase 1 (LSD1). Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):13956-61. Epub 2006 Sep 6. PMID:16956976