and PWWP domains, which recognize histones and other proteins harboring
a methylated lysine and also a methylated arginine for the Tudor domain.
The recognition of these posttranslational modifications by Royal Family proteins
affects many key cellular processes such as chromatin condensation, DNA transcription, gene silencing, the maintenance of epigenetic expression states, and
the DNA damage response. Proteins of the Royal Family usually function in
the context of large assemblies typically composed of one or more enzymes
and several nonenzymatic subunits. A case in point is that of the evolutionarily
conserved SAGA (SPT-ADA-GCN5-acetyltransferase) complex, made of more
than 20 proteins, which facilitates DNA transcription [56]. The tandem Tudor
domains of a subunit of SAGA, namely, SGF29 (SAGA-associated factor of
29 kDa), recognize H3K4me3, a signal for gene transcription. Binding of SGF29
to H3K4me3 contributes to the recruitment of SAGA to chromatin and thereby
allows acetylation of H3 at lysines 9, 14, and 18 by SAGA subunit GCN5 (general
control non-derepressible 5, also known as KAT2A), which promotes gene
transcription [57].
The members of the Royal Family show structural similarity, and they all have
a similar structural fold in common. Four of them (Tudor, MBT, chromo-barrel,
and PWWP domains) fold into a roughly 60 amino acid SRC homology 3-like
(SH3-like) antiparallel five-stranded twisted β-barrel structure and differ mainly
by the number and relative orientations of the β-barrels as well as added
secondary structure elements. The first Royal Family structure with a five-stranded
β-barrel core motif to be determined was that of the single Tudor domain of
human SMN (survival motor neuron) protein which was later shown to recognize
a methylarginine [58, 59]. As mentioned above, a defining feature of the Royal
Family proteins is an aromatic-binding cage that can accommodate a methyllysine or
a methylarginine. A well-characterized example is the complex of 53BP1 tandem
Tudor domains with histone H4 methylated at lysine 20 [60].
The chromodomain (chromatin organization modifier domain) differs from other
Royal Family members in that in its simplest form it is constituted of a three-stranded
antiparallel β-sheet packed against a C-terminal α-helix and does not adopt a barrel
structure [61]. A lysine may be mono-, di-, or trimethylated at the ε-amino group
(also referred to as the Nζ position). Regardless of the methylation state, the main
driving force for methyllysine recognition comes from cation-π interactions between
the methylammonium cation and surrounding aromatic residues in the binding cage
[62]. For higher methylation states, there is also a significant contribution of
the hydrophobic desolvation effect to methyllysine recognition [63]. Some Royal
Family domains can selectively recognize a mono- or dimethyllysine and exclude
a trimethyllysine. In these domains, a hydrogen bond and an ion-pair interaction
between the methylammonium cation and a carboxylate group in the aromatic cage
contribute to binding stability and methylation-state specificity.
Methyl-Readers and Inhibitors
349
a methylated lysine and also a methylated arginine for the Tudor domain.
The recognition of these posttranslational modifications by Royal Family proteins
affects many key cellular processes such as chromatin condensation, DNA transcription, gene silencing, the maintenance of epigenetic expression states, and
the DNA damage response. Proteins of the Royal Family usually function in
the context of large assemblies typically composed of one or more enzymes
and several nonenzymatic subunits. A case in point is that of the evolutionarily
conserved SAGA (SPT-ADA-GCN5-acetyltransferase) complex, made of more
than 20 proteins, which facilitates DNA transcription [56]. The tandem Tudor
domains of a subunit of SAGA, namely, SGF29 (SAGA-associated factor of
29 kDa), recognize H3K4me3, a signal for gene transcription. Binding of SGF29
to H3K4me3 contributes to the recruitment of SAGA to chromatin and thereby
allows acetylation of H3 at lysines 9, 14, and 18 by SAGA subunit GCN5 (general
control non-derepressible 5, also known as KAT2A), which promotes gene
transcription [57].
The members of the Royal Family show structural similarity, and they all have
a similar structural fold in common. Four of them (Tudor, MBT, chromo-barrel,
and PWWP domains) fold into a roughly 60 amino acid SRC homology 3-like
(SH3-like) antiparallel five-stranded twisted β-barrel structure and differ mainly
by the number and relative orientations of the β-barrels as well as added
secondary structure elements. The first Royal Family structure with a five-stranded
β-barrel core motif to be determined was that of the single Tudor domain of
human SMN (survival motor neuron) protein which was later shown to recognize
a methylarginine [58, 59]. As mentioned above, a defining feature of the Royal
Family proteins is an aromatic-binding cage that can accommodate a methyllysine or
a methylarginine. A well-characterized example is the complex of 53BP1 tandem
Tudor domains with histone H4 methylated at lysine 20 [60].
The chromodomain (chromatin organization modifier domain) differs from other
Royal Family members in that in its simplest form it is constituted of a three-stranded
antiparallel β-sheet packed against a C-terminal α-helix and does not adopt a barrel
structure [61]. A lysine may be mono-, di-, or trimethylated at the ε-amino group
(also referred to as the Nζ position). Regardless of the methylation state, the main
driving force for methyllysine recognition comes from cation-π interactions between
the methylammonium cation and surrounding aromatic residues in the binding cage
[62]. For higher methylation states, there is also a significant contribution of
the hydrophobic desolvation effect to methyllysine recognition [63]. Some Royal
Family domains can selectively recognize a mono- or dimethyllysine and exclude
a trimethyllysine. In these domains, a hydrogen bond and an ion-pair interaction
between the methylammonium cation and a carboxylate group in the aromatic cage
contribute to binding stability and methylation-state specificity.
Methyl-Readers and Inhibitors
349