Crystal structure of human histone lysine-specific demethylase 1 (LSD1).
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.
Chen
Yong
Y
Department of Biological Chemistry, University of Michigan Medical School, 5413 Medical Science I, 1301 Catherine Road, Ann Arbor, MI 48109-0606, USA.
Yang
Yuting
Y
Wang
Feng
F
Wan
Ke
K
Yamane
Kenichi
K
Zhang
Yi
Y
Lei
Ming
M
D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D056466:Histone Demethylases; D006657:Histones / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010089:Oxidoreductases, N-Demethylating / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
D006657:Histones; D056466:Histone Demethylases; C495195:KDM1A protein, human; D010089:Oxidoreductases, N-Demethylating