against the core subunit of another repeat. This generates different spatial organizations of the MBT repeats in different proteins. For example, the three MBT domains
of L3MBTL1 adopt a triangular propeller-like architecture where the arm of the first
MBT domain contacts the core of the third MBT domain. Structurally, MBT proteins
are comprised of two, three, or four MBT domains (MBT1, MBT2, MBT3, MBT4)
flanked by other domains such as a zinc finger and/or sterile alpha motif (SAM)
[4, 165]. Interestingly, while each MBT-containing protein has multiple MBT
domains, only one domain contains the functional aromatic cage that can recognize
and bind methylated lysine residues [166, 167].
The cellular functions containing two (such as SCML2) or four (such as
L3MBTL2 and Sfbmt) MBT repeats are still poorly understood from a biological
point of view. Therefore they will not be discussed further in this more chemical
oriented book chapter [168].
4.4.1 Proteins Containing Three MBT Repeats (L3MBTL1
and L3MBTL3)
4.4.1.1 Structure and Function
The first structures of MBT complexes to be reported were those of human
L3BMTL1 bound to H4K20me1, H4K20me2, and H1.5K27me2 peptides and
single mono- and dimethylated lysines [166]. Only the methylated lysine of
H4K20me1, H4K20me2, or H1.5K27me2 contacts extensively L3MBTL1. This
is consistent with the relatively low affinity (K D ¼ ~5 μM for H4K20me1 or
H4K20me2) and especially low specificity of this protein. Several other mono- or
dimethylated histone peptides such as H1bK26, H3K4, H3K9, and H3K27 bind
L3MBTL1 with similar K D s [166]. Human L3MBTL1 seems to play multiple roles
in the cell although a clear function remains to be determined. It was initially
characterized as a transcriptional repressor, and the three MBT domains were
shown to be essential for this gene-silencing function [169]. Transcriptional repression requires that L3MBTL1 associates with histones in a mono- or dimethylationdependent manner at H4K20 or H1bK26, which leads to chromatin condensation
at retinoblastoma protein-regulated genes [170].
L3MBTL3, a close homolog of L3MBTL1, is a relatively uncharacterized
member of the human MBT family. It also contains three MBT domains but differs
from L3MBTL1 in what lysine methylation marks it recognizes. While L3MBTL1
recognizes Kme1 and Kme2 on H2B, H3, and H4, L3MBTL3 exclusively binds to
Kme2 marks on these histones [165]. Additionally, L3MBTL1 has been shown
to bind nonhistone targets like the tumor suppressor protein p53 (p53K382me1).
Unlike other members of the MBT family, both L3MBTL1 and L3MBTL3 are
nonselective readers of lysine methylation that do not recognize histone peptides
in a sequence-selective manner [171]. Furthermore, L3MBTL1 has been described
as a “chromatin lock” with the ability to negatively regulate the expression of E2F
regulated genes like c-myc through the binding of the retinoblastoma protein (pRb)
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G. Sbardella
of L3MBTL1 adopt a triangular propeller-like architecture where the arm of the first
MBT domain contacts the core of the third MBT domain. Structurally, MBT proteins
are comprised of two, three, or four MBT domains (MBT1, MBT2, MBT3, MBT4)
flanked by other domains such as a zinc finger and/or sterile alpha motif (SAM)
[4, 165]. Interestingly, while each MBT-containing protein has multiple MBT
domains, only one domain contains the functional aromatic cage that can recognize
and bind methylated lysine residues [166, 167].
The cellular functions containing two (such as SCML2) or four (such as
L3MBTL2 and Sfbmt) MBT repeats are still poorly understood from a biological
point of view. Therefore they will not be discussed further in this more chemical
oriented book chapter [168].
4.4.1 Proteins Containing Three MBT Repeats (L3MBTL1
and L3MBTL3)
4.4.1.1 Structure and Function
The first structures of MBT complexes to be reported were those of human
L3BMTL1 bound to H4K20me1, H4K20me2, and H1.5K27me2 peptides and
single mono- and dimethylated lysines [166]. Only the methylated lysine of
H4K20me1, H4K20me2, or H1.5K27me2 contacts extensively L3MBTL1. This
is consistent with the relatively low affinity (K D ¼ ~5 μM for H4K20me1 or
H4K20me2) and especially low specificity of this protein. Several other mono- or
dimethylated histone peptides such as H1bK26, H3K4, H3K9, and H3K27 bind
L3MBTL1 with similar K D s [166]. Human L3MBTL1 seems to play multiple roles
in the cell although a clear function remains to be determined. It was initially
characterized as a transcriptional repressor, and the three MBT domains were
shown to be essential for this gene-silencing function [169]. Transcriptional repression requires that L3MBTL1 associates with histones in a mono- or dimethylationdependent manner at H4K20 or H1bK26, which leads to chromatin condensation
at retinoblastoma protein-regulated genes [170].
L3MBTL3, a close homolog of L3MBTL1, is a relatively uncharacterized
member of the human MBT family. It also contains three MBT domains but differs
from L3MBTL1 in what lysine methylation marks it recognizes. While L3MBTL1
recognizes Kme1 and Kme2 on H2B, H3, and H4, L3MBTL3 exclusively binds to
Kme2 marks on these histones [165]. Additionally, L3MBTL1 has been shown
to bind nonhistone targets like the tumor suppressor protein p53 (p53K382me1).
Unlike other members of the MBT family, both L3MBTL1 and L3MBTL3 are
nonselective readers of lysine methylation that do not recognize histone peptides
in a sequence-selective manner [171]. Furthermore, L3MBTL1 has been described
as a “chromatin lock” with the ability to negatively regulate the expression of E2F
regulated genes like c-myc through the binding of the retinoblastoma protein (pRb)
364
G. Sbardella