4EDU

The MBT repeats of human SCML2 in a complex with histone H2A peptide

Summary for 4EDU

• Entry DOI: 10.2210/pdb4edu/pdb
• Descriptor: Sex comb on midleg-like protein 2, Histone H2A.J peptide (3 entities in total)
• Functional Keywords: mbt fold, royal family, histone ptm binding, methylation, transcription
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus : Q9UQR0 Q9BTM1
• Total number of polymer chains: 2
• Total formula weight: 25989.47

Authors

Nady, N.,Amaya, M.F.,Tempel, W.,Ravichandran, M.,Arrowsmith, C.H. (deposition date: 2012-03-27, release date: 2012-09-19, Last modification date: 2023-09-13)

Primary citation

Nady, N.,Krichevsky, L.,Zhong, N.,Duan, S.,Tempel, W.,Amaya, M.F.,Ravichandran, M.,Arrowsmith, C.H.
Histone recognition by human malignant brain tumor domains.
J.Mol.Biol., 423:702-718, 2012

PubMed Abstract: Histone methylation has emerged as an important covalent modification involved in a variety of biological processes, especially regulation of transcription and chromatin dynamics. Lysine methylation is found in three distinct states (monomethylation, dimethylation and trimethylation), which are recognized by specific protein domains. The malignant brain tumor (MBT) domain is one such module found in several chromatin regulatory complexes including Polycomb repressive complex 1. Here, we present a comprehensive characterization of the human MBT family with emphasis on histone binding specificity. SPOT-blot peptide arrays were used to screen for the methyllysine-containing histone peptides that bind to MBT domains found in nine human proteins. Selected interactions were quantified using fluorescence polarization assays. We show that all MBT proteins recognize only monomethyllysine and/or dimethyllysine marks and provide evidence that some MBT domains recognize a defined consensus sequence while others bind in a promiscuous, non-sequence-specific manner. Furthermore, using structure-based mutants, we identify a triad of residues in the methyllysine binding pocket that imparts discrimination between monomethyllysine and dimethyllysine. This study represents a comprehensive analysis of MBT substrate specificity, establishing a foundation for the rational design of selective MBT domain inhibitors that may enable elucidation of their role in human biology and disease.

PubMed: 22954662
DOI: 10.1016/j.jmb.2012.08.022

Experimental method

X-RAY DIFFRACTION (2.58 Å)