Structural studies of a four-MBT repeat protein MBTD1.
BACKGROUND
The Polycomb group (PcG) of proteins is a family of important developmental regulators. The respective members function as large protein complexes involved in establishment and maintenance of transcriptional repression of developmental control genes. MBTD1, Malignant Brain Tumor domain-containing protein 1, is one such PcG protein. MBTD1 contains four MBT repeats.


RESULTS
We have determined the crystal structure of MBTD1 (residues 130-566aa covering the 4 MBT repeats) at 2.5 A resolution by X-ray crystallography. The crystal structure of MBTD1 reveals its similarity to another four-MBT-repeat protein L3MBTL2, which binds lower methylated lysine histones. Fluorescence polarization experiments confirmed that MBTD1 preferentially binds mono- and di-methyllysine histone peptides, like L3MBTL1 and L3MBTL2. All known MBT-peptide complex structures characterized to date do not exhibit strong histone peptide sequence selectivity, and use a "cavity insertion recognition mode" to recognize the methylated lysine with the deeply buried methyl-lysine forming extensive interactions with the protein while the peptide residues flanking methyl-lysine forming very few contacts [1]. Nevertheless, our mutagenesis data based on L3MBTL1 suggested that the histone peptides could not bind to MBT repeats in any orientation.


CONCLUSIONS
The four MBT repeats in MBTD1 exhibits an asymmetric rhomboid architecture. Like other MBT repeat proteins characterized so far, MBTD1 binds mono- or dimethylated lysine histones through one of its four MBT repeats utilizing a semi-aromatic cage.


BACKGROUND
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Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
Jitka
J
Eryilmaz
Patricia
P
Pan
Maria F
MF
Amaya
Abdellah
A
Allali-Hassani
Aiping
A
Dong
Melanie A
MA
Adams-Cioaba
Farrell
F
Mackenzie
Masoud
M
Vedadi
Jinrong
J
Min
D000595:Amino Acid Sequence; D001120:Arginine / Q000737:chemistry; D002843:Chromatin / Q000737:chemistry; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry*; D006657:Histones / Q000737:chemistry; D006801:Humans; D008239:Lysine / Q000737:chemistry; D008745:Methylation; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009707:Nucleosomes / Q000378:metabolism; D063146:Polycomb-Group Proteins; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid
D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; C546112:MBTD1 protein, human; D009707:Nucleosomes; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D001120:Arginine; D008239:Lysine