4.3 The Tudor Domain
At around the same time that the chromodomain-containing protein HP1 was
discovered as the first “reader” of a methyllysine mark on histone tails [16, 17],
the Tudor domain of survival motor neuron protein (SMN1) was characterized as
a methylarginine-binding module [59, 95]. Subsequent work revealed that Tudor
domains do not only bind methylarginine motifs but also interact with methyllysine
motifs [96–98]. Based on the primary amino acid sequence alignment of different
Tudor family members, it is not possible to predict whether the Tudor domain
belongs to the methyllysine- or methylarginine-binding family or what degree
(Kme1, Kme2, or Kme3) or type (Rme1, Rme2s, or Rme2a) of methylation is
recognized by a particular domain. As mentioned above, only recently structural
insight has been gained into the interaction of Tudor domains with their specific
methylarginine motif ligands [99–104] and suggested that the aromatic cage of
the methylarginine binders is narrower than that of methyllysine binders, which
favors the docking of the planar methyl-guanidinium group of arginine [102].
In mammals, there are at least 41 proteins that harbor Tudor domains [105],
and many of these proteins contain multiple copies of this domain. This structurally
diverse family of Tudor domain-containing proteins can be divided into three
groups: proteins with a single Tudor domain, tandem Tudor domains, and hybrid
Tudor domains.
4.3.1 Single Tudor Domain (PHF1, PHF19, PHF20)
4.3.1.1 Structure and Function
The best-characterized single Tudor domains are from the proteins plant
homeodomain finger 1 and 19 (PHF1 and PHF19), two components of the
Polycomb-like complex (PCL) in mammals. The PCL proteins regulate the
Polycomb-repressive complex PRC2 (Polycomb-repressive complex 2) by
recruiting PRC2 to its target genes where it triggers transcriptional silencing
by trimethylation of H3K27. Although not fully understood, the mechanism
involves the recognition by the Tudor domains of PHF1 and PHF19 of histone
H3 di- or trimethylated at lysine 36 (H3K36me2/3), which are markers of transcriptionally active genes. This brings PRC1/PHF1 or PRC2/PHF19 complexes and
associated H3K36me2/3 demethylases NO66 and KDM2B, and H3K4me3
demethylase KDM2A to target genes. Following H3K36me2/3 and H3K4me3
demethylation, PRC2 trimethylates H3K27, which leads to de novo gene silencing
[106–108]. The structures of the complexes of PHF1-Tudor and PHF19-Tudor
bound to an H3K36me3 peptide revealed the binding mechanism of a single
Tudor domain [106–108]. Another single Tudor domain characterized structurally
in complex with a methylated peptide is from human PHF20 (plant homeodomain
356
G. Sbardella
At around the same time that the chromodomain-containing protein HP1 was
discovered as the first “reader” of a methyllysine mark on histone tails [16, 17],
the Tudor domain of survival motor neuron protein (SMN1) was characterized as
a methylarginine-binding module [59, 95]. Subsequent work revealed that Tudor
domains do not only bind methylarginine motifs but also interact with methyllysine
motifs [96–98]. Based on the primary amino acid sequence alignment of different
Tudor family members, it is not possible to predict whether the Tudor domain
belongs to the methyllysine- or methylarginine-binding family or what degree
(Kme1, Kme2, or Kme3) or type (Rme1, Rme2s, or Rme2a) of methylation is
recognized by a particular domain. As mentioned above, only recently structural
insight has been gained into the interaction of Tudor domains with their specific
methylarginine motif ligands [99–104] and suggested that the aromatic cage of
the methylarginine binders is narrower than that of methyllysine binders, which
favors the docking of the planar methyl-guanidinium group of arginine [102].
In mammals, there are at least 41 proteins that harbor Tudor domains [105],
and many of these proteins contain multiple copies of this domain. This structurally
diverse family of Tudor domain-containing proteins can be divided into three
groups: proteins with a single Tudor domain, tandem Tudor domains, and hybrid
Tudor domains.
4.3.1 Single Tudor Domain (PHF1, PHF19, PHF20)
4.3.1.1 Structure and Function
The best-characterized single Tudor domains are from the proteins plant
homeodomain finger 1 and 19 (PHF1 and PHF19), two components of the
Polycomb-like complex (PCL) in mammals. The PCL proteins regulate the
Polycomb-repressive complex PRC2 (Polycomb-repressive complex 2) by
recruiting PRC2 to its target genes where it triggers transcriptional silencing
by trimethylation of H3K27. Although not fully understood, the mechanism
involves the recognition by the Tudor domains of PHF1 and PHF19 of histone
H3 di- or trimethylated at lysine 36 (H3K36me2/3), which are markers of transcriptionally active genes. This brings PRC1/PHF1 or PRC2/PHF19 complexes and
associated H3K36me2/3 demethylases NO66 and KDM2B, and H3K4me3
demethylase KDM2A to target genes. Following H3K36me2/3 and H3K4me3
demethylation, PRC2 trimethylates H3K27, which leads to de novo gene silencing
[106–108]. The structures of the complexes of PHF1-Tudor and PHF19-Tudor
bound to an H3K36me3 peptide revealed the binding mechanism of a single
Tudor domain [106–108]. Another single Tudor domain characterized structurally
in complex with a methylated peptide is from human PHF20 (plant homeodomain
356
G. Sbardella