Crystal Structure of Human Histone Lysine-specific Demethylase 1 (LSD1)

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2006 Sep 8

PMID 16956976

Citations 124

Authors

Yong Chen

Yuting Yang

Feng Wang

Ke Wan

Kenichi Yamane

Yi Zhang

Ming Lei

Affiliations

Soon will be listed here.

Abstract

Lysine-specific demethylase 1 (LSD1) was recently identified as the first histone demethylase that specifically demethylates monomethylated and dimethylated histone H3 at K4. It is a component of the CoREST and other corepressor complexes and plays an important role in silencing neuronal-specific genes in nonneuronal cells, but the molecular mechanisms of its action remain unclear. The 2.8-A-resolution crystal structure of the human LSD1 reveals that LSD1 defines a new subfamily of FAD-dependent oxidases. The active center of LSD1 is characterized by a remarkable 1,245-A3 substrate-binding cavity with a highly negative electrostatic potential. Although the protein core of LSD1 resembles other flavoenzymes, its enzymatic activity and functions require two additional structural modules: an N-terminal SWIRM domain important for protein stability and a large insertion in the catalytic domain indispensable both for the demethylase activity and the interaction with CoREST. These results provide a framework for further probing the catalytic mechanism and the functional roles of LSD1.

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References

Ballas N, Battaglioli E, Atouf F, Andres M, Chenoweth J, Anderson M . Regulation of neuronal traits by a novel transcriptional complex. Neuron. 2001; 31(3):353-65. DOI: 10.1016/s0896-6273(01)00371-3. View

Binda C, Newton-Vinson P, Hubalek F, Edmondson D, Mattevi A . Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders. Nat Struct Biol. 2001; 9(1):22-6. DOI: 10.1038/nsb732. View

Yamane K, Toumazou C, Tsukada Y, Erdjument-Bromage H, Tempst P, Wong J . JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell. 2006; 125(3):483-95. DOI: 10.1016/j.cell.2006.03.027. View

Shi Y, Lan F, Matson C, Mulligan P, Whetstine J, Cole P . Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 2004; 119(7):941-53. DOI: 10.1016/j.cell.2004.12.012. View

Brunger A, Adams P, Clore G, DeLano W, Gros P, Grosse-Kunstleve R . Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr D Biol Crystallogr. 1998; 54(Pt 5):905-21. DOI: 10.1107/s0907444998003254. View

Da G, Lenkart J, Zhao K, Shiekhattar R, Cairns B, Marmorstein R . Structure and function of the SWIRM domain, a conserved protein module found in chromatin regulatory complexes. Proc Natl Acad Sci U S A. 2006; 103(7):2057-62. PMC: 1413740. DOI: 10.1073/pnas.0510949103. View

Shi Y, Matson C, Lan F, Iwase S, Baba T, Shi Y . Regulation of LSD1 histone demethylase activity by its associated factors. Mol Cell. 2005; 19(6):857-64. DOI: 10.1016/j.molcel.2005.08.027. View

Lee M, Wynder C, Cooch N, Shiekhattar R . An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature. 2005; 437(7057):432-5. DOI: 10.1038/nature04021. View

Tochio N, Umehara T, Koshiba S, Inoue M, Yabuki T, Aoki M . Solution structure of the SWIRM domain of human histone demethylase LSD1. Structure. 2006; 14(3):457-68. DOI: 10.1016/j.str.2005.12.004. View

10.

Humphrey G, Wang Y, Russanova V, Hirai T, Qin J, Nakatani Y . Stable histone deacetylase complexes distinguished by the presence of SANT domain proteins CoREST/kiaa0071 and Mta-L1. J Biol Chem. 2000; 276(9):6817-24. DOI: 10.1074/jbc.M007372200. View

11.

Aravind L, Iyer L . The SWIRM domain: a conserved module found in chromosomal proteins points to novel chromatin-modifying activities. Genome Biol. 2002; 3(8):RESEARCH0039. PMC: 126233. DOI: 10.1186/gb-2002-3-8-research0039. View

12.

Martin C, Zhang Y . The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol. 2005; 6(11):838-49. DOI: 10.1038/nrm1761. View

13.

Binda C, Angelini R, Federico R, Ascenzi P, Mattevi A . Structural bases for inhibitor binding and catalysis in polyamine oxidase. Biochemistry. 2001; 40(9):2766-76. DOI: 10.1021/bi002751j. View

14.

Shi Y, Sawada J, Sui G, Affar E, Whetstine J, Lan F . Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature. 2003; 422(6933):735-8. DOI: 10.1038/nature01550. View

15.

Tsukada Y, Fang J, Erdjument-Bromage H, Warren M, Borchers C, Tempst P . Histone demethylation by a family of JmjC domain-containing proteins. Nature. 2005; 439(7078):811-6. DOI: 10.1038/nature04433. View

16.

Qian C, Zhang Q, Li S, Zeng L, Walsh M, Zhou M . Structure and chromosomal DNA binding of the SWIRM domain. Nat Struct Mol Biol. 2005; 12(12):1078-85. DOI: 10.1038/nsmb1022. View

17.

Kleeberg U, Klinger W . Sensitive formaldehyde determination with Nash's reagent and a 'tryptophan reaction'. J Pharmacol Methods. 1982; 8(1):19-31. DOI: 10.1016/0160-5402(82)90004-3. View

18.

Hakimi M, Dong Y, Lane W, Speicher D, Shiekhattar R . A candidate X-linked mental retardation gene is a component of a new family of histone deacetylase-containing complexes. J Biol Chem. 2002; 278(9):7234-9. DOI: 10.1074/jbc.M208992200. View

19.

Wierenga R, Drenth J, Schulz G . Comparison of the three-dimensional protein and nucleotide structure of the FAD-binding domain of p-hydroxybenzoate hydroxylase with the FAD- as well as NADPH-binding domains of glutathione reductase. J Mol Biol. 1983; 167(3):725-39. DOI: 10.1016/s0022-2836(83)80106-5. View

20.

Trojer P, Reinberg D . Histone lysine demethylases and their impact on epigenetics. Cell. 2006; 125(2):213-7. DOI: 10.1016/j.cell.2006.04.003. View