LIG_LSD1_SNAG_1

The Lysine-specific demethylase (LSD1) is a chromatin-modifying enzyme belonging to the FAD-dependent amine oxidase family (Forneris,2008). It reads different epigenetic marks on the histone proteins and suppresses gene expression by converting di-methylated H3K4 to mono- and un-methylated H3K4 through amine oxidation (Shi,2004). It is also involved in transcriptional activation of a subset of androgen or estrogen-responsive genes in co-operation with Androgen or Estrogen Receptor α (Carnesecchi,2017). LSD1 plays an essential role in transcriptional regulation, formation of repressive chromatin structure, embryonic development and tumour invasiveness (Chiang,2013).
LSD1 has been found in a number of repressor complexes and it functions together with a well-characterized repressive motif, termed the SNAG domain. (SNAG is actually a short linear motif, not a globular domain). LSD1 interacts with the SNAG motif of several transcription factors including SNAIL, Gfi-1 and Insm1 (Chiang,2013). The SNAG motif of these transcription factors partially resembles the N-terminal region of histone H3. It acts as a ‘hook’ or pseudosubstrate to interact with the LSD1–CoREST–HDAC complex. Studies have shown that LSD1 binds SNAG with high affinity and becomes recruited to the target gene promoter for repressor activity. The high local concentrations of histone H3 tails compete with SNAG binding and release LSD1 to demethylate the bona fide substrate H3K4me2 and, together with SNAIL, supports the repression of target genes (Baron,2011). In many transcriptional repression mechanisms, the SNAG motif of the corresponding transcriptional factors brings this complex to its target gene promoters where it binds a specific hexanucleotide sequence through the zinc-finger motifs of the transcription factors and represses the gene expression. One of the commonly identified hexanucleotides in SNAG family transcription factors is termed the E-box (Chiang,2013).

The C-terminal amine oxidase (AO) domain of LSD1 is the catalytic moiety that demethylates the histone H3 lysines and also interacts with SNAG found in the zinc finger and homeobox transcription factors. The amino oxidase domain of LSD1 is separated by a tower domain from the FAD co-enzyme binding site and the substrate recognition site. The tower domain is required for CoREST binding and allosterically modulates the interaction of the FAD‐binding lobe with the substrate‐binding lobe of LSD1 and thus controls the demethylase activity of LSD1 (Forneris,2008).
The SNAG motif is a highly conserved region located at the very N-terminus of these TFs and often associated with dimethylated arginine or lysine nearby that is essential for its interaction with LSD1–CoREST (Laurent,2012). The repressive function of Snail SNAG is conserved among vertebrates whereas Drosophila Snail lacks the SNAG domain but still functions as a transcriptional repressor, through interaction with a well-characterized co-repressor, CtBP (carboxy-terminal binding protein) (LIG_CtBP_PxDLS_1).
Many of the snail superfamily members are involved in numerous developmental processes as well as in diseases. Snail and LSD1 repressor complex downregulates E-cadherin transcription and induces epithelial-mesenchymal transition (EMT) that is observed in embryonic development and tumour progression (Lin,2014). In the case of Insm1, the SNAG motif is involved in the development of pituitary endocrine cells (Welcker,2013), while the Gfi-1 family SNAG motif controls hematopoietic differentiation (Saleque,2007).