The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Functional site class:
LSD1 binding SNAG inhibitory motif
Functional site description:
The Lysine-Specific Demethylase (LSD1, also known as KDM1A) is a component of the transcriptional repressor complex LSD1–CoREST–HDAC (LCH complex). It represses transcription by catalyzing histone (H3K4) demethylation. LSD1 is docked to promoters by pre-bound transcription factors. The amine oxidase domain of LSD1 binds to the transcription factors through a highly conserved N-terminal sequence known as the SNAG (for Snail/Gfi) domain. This motif is mainly observed among vertebrate zinc finger and homeobox transcription factors and accounts for repressive functions and protein stability. The activities of these TFs are multifaceted, ranging from developmental to disease state. Many of the SNAG motif-containing proteins regulate EMT in developmental stages and also in cancerous cells. LSD1 is associated with a variety of cancers, making it a candidate therapeutic target to block tumour progression.
ELM Description:
Vertebrate LSD1 is recruited to target gene promoters by interacting with the SNAG motif present in various transcription factors such as SNAIL family members, Gfi-1, Insm1 and Ovo‐like 1 (OVOL1). The SNAG motif shows partial similarity to the Histone H3 N-terminal sequence and binds to the LSD1 active site in a conformation similar to that of the H3 tail. The SNAG motif in these transcription factors act as a molecular hook to bring the LSD1 to the promoter site. SNAG docks into the active site and is inhibitory. After release from SNAG, LSD1 demethylates the lysine 4 on histone 3 (H3K4) or lysine 9 (H3K9).
The minimal SNAG motif is a circa eight amino acid length sequence highly conserved in the very N-terminal region of these TFs, with the N-terminal methionine cleaved off as usual. The amine oxidase (AO) domain of LSD1 is responsible for its interaction with SNAG. In histone H3, the residues at the positions Arg2, Thr6, Arg8, Lys9, and Thr11 are critical for binding as LSD1 substrate (Lin,2010) and the SNAG domain of other transcription factors shares identical residues at positions Arg3, Arg8, and Lys9 and make similar contacts with LSD1. Structural and mutational studies (Baron,2011; Lin,2010) of the Snail SNAG-LSD1 complex show that Pro2, Arg3, Ser4, Phe5, Arg8 and Lys9 of Snail are important for making contacts with LSD1. The N-terminal amino group of Pro2 H-bonds with the carbonyl of Ala539 and its side chain makes hydrophobic interactions in the pocket. Side chains of Arg3 and Ser4 bind deeply into the LSD1 cleft and make several H-bonding interactions with the surrounding protein residues. Phe5 snugly fits in its binding niche by making hydrophobic edge-to-face interactions with the rings of the flavin cofactor and Tyr761. In the H3 substrate, the corresponding position is replaced by the dimethylated lysine. The Arg8 and Lys9 residues make salt bridges and electrostatic interaction with LSD1 respectively (Forneris,2007).
Pattern: ^M{0,1}PR.FLV[KR]K{0,1}.
Pattern Probability: 8.862e-11
Present in taxons: Chordata Vertebrata
Interaction Domain:
Amino_oxidase (PF01593) Flavin containing amine oxidoreductase (Stochiometry: 1 : 1)
o See 11 Instances for LIG_LSD1_SNAG_1
o Abstract
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).
o 15 selected references:

o 12 GO-Terms:

o 11 Instances for LIG_LSD1_SNAG_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
1 10 MPRSFLVKKIKGDGFQCSGV TP 1 Homo sapiens (Human)
Q96T92 INSM2
1 9 MPRGFLVKRTKRTGGLYRVR TP 1 Homo sapiens (Human)
Q9QY31 Snai3
1 9 MPRSFLVKTHSSHRVPNYGK TP 1 Mus musculus (House mouse)
O14753 OVOL1
1 10 MPRAFLVKKPCVSTCKRNWS TP 2 Homo sapiens (Human)
O95863 SNAI1
1 10 MPRSFLVRKPSDPNRKPNYS TP 9 Homo sapiens (Human)
1 10 MPRSFLVKKVKLDAFSSADL TP 1 Homo sapiens (Human)
O43623 SNAI2
1 10 MPRSFLVKKHFNASKKPNYS TP 3 Homo sapiens (Human)
Q63ZV0 Insm1
1 9 MPRGFLVKRSKKSTPVSYRV TP 2 Mus musculus (House mouse)
1 9 MPRSFLVKSKKAHTYHQPRV TP 5 Homo sapiens (Human)
P70338 Gfi1
1 9 MPRSFLVKSKKAHSYHQPRS TP 4 Mus musculus (House mouse)
O70237 Gfi1b
1 9 MPRSFLVKSKKAHTYHQPRA TP 4 Mus musculus (House mouse)
Please cite: ELM — the eukaryotic linear motif resource in 2020. (PMID:31680160)

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