BACKGROUND: M-phase phosphoprotein 8 (MPP8) was initially identified to be a 
component of the RanBPM-containing large protein complex, and has recently been 
shown to bind to methylated H3K9 both in vivo and in vitro. MPP8 binding to 
methylated H3K9 is suggested to recruit the H3K9 methyltransferases GLP and 
ESET, and DNA methyltransferase 3A to the promoter of the E-cadherin gene, 
mediating the E-cadherin gene silencing and promote tumor cell motility and 
invasion. MPP8 contains a chromodomain in its N-terminus, which is used to bind 
the methylated H3K9.
METHODOLOGY/PRINCIPAL FINDINGS: Here, we reported the crystal structures of 
human MPP8 chromodomain alone and in complex with the trimethylated histone H3K9 
peptide (residue 1-15). The complex structure unveils that the human MPP8 
chromodomain binds methylated H3K9 through a conserved recognition mechanism, 
which was also observed in Drosophila HP1, a chromodomain containing protein 
that binds to methylated H3K9 as well. The structure also reveals that the human 
MPP8 chromodomain forms homodimer, which is mediated via an unexpected domain 
swapping interaction through two β strands from the two protomer subunits.
CONCLUSIONS/SIGNIFICANCE: Our findings reveal the molecular mechanism of 
selective binding of human MPP8 chromodomain to methylated histone H3K9. The 
observation of human MPP8 chromodomain in both solution and crystal lattice may 
provide clues to study MPP8-mediated gene regulation furthermore.