Histone Recognition by Human Malignant Brain Tumor Domains

Solution NMR Structure of the DNA-binding Domain from Scml2 (Sex Comb on Midleg-like 2)

“…Remarkably, previous studies have shown that the full-length Scml2 can effectively bind DNA in a manner independent of its MBT domains, which is in agreement with results shown here (18). It was also suggested that Scml2 may contain a DNAbinding motif similar to an AT-hook that is responsible for DNA binding (18).…”

“…Indeed, a number of structures of MBT domains were solved in complexes with peptides containing methylated lysine residues (11)(12)(13)(14)(15)(16)(17)(18), including structures of two MBT domains from Scml2. The structures of MBT domains and biochemical analyses of their binding specificities revealed that they weakly interact with mono-and dimethylated lysine residues through a conserved site with affinities ranging from 30 M to 1 mM (18). Most MBT domains are promiscuous binders that associate with mono-and dimethylated lysines regardless of their sequence context, whereas some have a preference for a specific methylated substrate (18).…”

“…The structures of MBT domains and biochemical analyses of their binding specificities revealed that they weakly interact with mono-and dimethylated lysine residues through a conserved site with affinities ranging from 30 M to 1 mM (18). Most MBT domains are promiscuous binders that associate with mono-and dimethylated lysines regardless of their sequence context, whereas some have a preference for a specific methylated substrate (18). However, in almost all cases, MBT repeats recognize only lower methylation states of the histone lysines.…”

Chromatin regulation: How complex does it get?

“…41 In vitro studies using isolated MBT domains and histone peptides have demonstrated a general preference for binding to mono-or di-methylated, over un-or tri-methylated peptides. 27,[42][43][44][45][46][47][48][49] An exception to this general rule is provided by the Caenorhabditis elegans protein LIN-61, which displays specificity toward di-and tri-methylated H3K9 histone peptides. 50 A recent study investigating the MBT domains of all 9 human family members has found that some MBT domains (L3MBTL1, L3MBTL3) recognize mono-and/or di-methyl-lysine in a promiscuous, non-sequence-specific fashion, whereas others (SCML2, L3MBTL4, MBTD1, L3MBTL2) specifically bind to only a few selected histone sequences.…”

“…50 A recent study investigating the MBT domains of all 9 human family members has found that some MBT domains (L3MBTL1, L3MBTL3) recognize mono-and/or di-methyl-lysine in a promiscuous, non-sequence-specific fashion, whereas others (SCML2, L3MBTL4, MBTD1, L3MBTL2) specifically bind to only a few selected histone sequences. 49 Studies focusing on L3MBTL1 and L3MBTL2 have revealed a possible molecular mechanism by which MBT domains could contribute to transcriptional repression. Incubation of the MBT domains of L3MBTL1 or of full-length L3MBTL2 with oligo-nucleosomal arrays results in chromatin compaction in vitro.…”