Methylation-state-specific recognition of histones by the MBT repeat protein L3MBTL2.
The MBT repeat has been recently identified as a key domain capable of methyl-lysine histone recognition. Functional work has pointed to a role for MBT domain-containing proteins in transcriptional repression of developmental control genes such as Hox genes. In this study, L3MBTL2, a human homolog of Drosophila Sfmbt critical for Hox gene silencing, is demonstrated to preferentially recognize lower methylation states of several histone-derived peptides through its fourth MBT repeat. High-resolution crystallographic analysis of the four MBT repeats of this protein reveals its unique asymmetric rhomboid architecture, as well as binding mechanism, which preclude the interaction of the first three MBT repeats with methylated peptides. Structural elucidation of an L3MBTL2-H4K20me1 complex and comparison with other MBT-histone peptide complexes also suggests that an absence of distinct surface contours surrounding the methyl-lysine-binding pocket may underlie the lack of sequence specificity observed for members of this protein family.
Guo
Yahong
Y
Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L6, Ontario, Canada.
Nady
Nataliya
N
Qi
Chao
C
Allali-Hassani
Abdellah
A
Zhu
Haizhong
H
Pan
Patricia
P
Adams-Cioaba
Melanie A
MA
Amaya
Maria F
MF
Dong
Aiping
A
Vedadi
Masoud
M
Schapira
Matthieu
M
Read
Randy J
RJ
Arrowsmith
Cheryl H
CH
Min
Jinrong
J
D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D020449:Repetitive Sequences, Amino Acid; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism
D006657:Histones; C439764:L3MBTL2 protein, human; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; D014157:Transcription Factors; D008239:Lysine