Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 38, Pages 13956-13961Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0606381103
Keywords
histone modification; flavoenzyme; catalysis
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Funding
- NIGMS NIH HHS [GM68804, R01 GM068804] Funding Source: Medline
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Lysine-specific demethylase 1 (LSD1) was recently identified as the first histone demethylase that specifically demethylates mono-methylated 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-angstrom-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-angstrom(3) 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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