New roles of flavoproteins in molecular cell biology: histone demethylase LSD1 and chromatin.
Lysine-specific demethylase 1 (LSD1) is an enzyme that removes methyl groups from mono- and dimethylated Lys4 of histone H3, a post-translational modification associated with gene activation. Human LSD1 was the first histone demethylase to be discovered and this enzymatic activity is conserved among eukaryotes. LSD1 has been identified in a number of chromatin-remodeling complexes that control gene transcription and its demethylase activity has also been linked to pathological processes including tumorigenesis. The 852-residue sequence of LSD1 comprises an amine oxidase domain which identifies a family of enzymes that catalyze the FAD-dependent oxidation of amine substrates ranging from amino acids to aromatic neurotransmitters. Among these proteins, LSD1 is peculiar in that it acts on a protein substrate in the nuclear environment of chromatin-remodeling complexes. This functional divergence occurred during evolution from the eubacteria to eukaryotes by acquisition of additional domains such as the SWIRM domain. The N-terminal part of LSD1, predicted to be disordered, contains linear motifs that might represent functional sites responsible for the association of this enzyme with a variety of transcriptional protein complexes. LSD1 shares structural features with other flavin amine oxidases, including the overall fold of the amine oxidase domain region and details in the active site that are relevant for amine substrate oxidation.
Forneris
Federico
F
Dipartimento di Genetica e Microbiologia, Università di Pavia, Italy.
Battaglioli
Elena
E
Mattevi
Andrea
A
Binda
Claudia
C
D000818:Animals; D001426:Bacterial Proteins; D002843:Chromatin / Q000378:metabolism*; D005420:Flavoproteins / Q000502:physiology*; D005656:Fungal Proteins; D005786:Gene Expression Regulation; D056466:Histone Demethylases; D006801:Humans; D008745:Methylation; D050891:Oxidoreductases Acting on CH-NH2 Group Donors; D010089:Oxidoreductases, N-Demethylating / Q000502:physiology*; D010940:Plant Proteins
D001426:Bacterial Proteins; D002843:Chromatin; D005420:Flavoproteins; D005656:Fungal Proteins; D010940:Plant Proteins; D056466:Histone Demethylases; D050891:Oxidoreductases Acting on CH-NH2 Group Donors; C495195:KDM1A protein, human; D010089:Oxidoreductases, N-Demethylating