To date, methylated lysines on histone tails appear to be targeted by the
largest and most diverse set of readers. This includes plant homeodomains (PHDs),
WD-40 domains, chromatin organization modifier domains (chromodomains, CDs),
double chromodomains (DCDs), chromo-barrel domains, ADD (ATRX-DNMT3DNMT3L) domains, ankyrin repeats (ANKs), proline-tryptophan-tryptophanproline (PWWP) domains, bromo adjacent homology (BAH) domains, chromo-barrel,
chromodomain (CD), double chromodomain (DCD), HEAT, malignant brain tumor
(MBT) domains, SAWADEE, Tudor domains, tandem Tudor domain (TTD), and zinc
finger CW (zf-CW) domains [4, 8, 19–21]. Some methyllysine readers, including PHD
and zf-CW, show a high degree of sequence specificity, while others, including MBT
and WD40, are more promiscuous though they can select for a certain methylation
state of a target lysine (Fig. 2). Despite the wide variety of the readers and histone
targets, the majority of these domains have comparable binding affinities, with dissociation constants of the complexes being in the high nanomolar to the low micromolar
range [19, 22].
On the other hand, the only protein domain family currently known to bind
methylated arginine motifs is the Tudor family (although individual PHD and
WD40 domains also harbor this ability) [8, 19].
The main feature of all methyllysine-binding domains identified so far is that
they bind this PTM through an aromatic cage, typically formed by two to four
aromatic residues. The exact composition and size of the pocket are responsible for
the selectivity for mono-, di-, or trimethylated state of lysine [19]. Specificity for a
particular methylated lysine is imparted by interaction with surrounding residues.
Some histone readers show high degrees of specificity, whereas others are selective
for only a certain methylation state and otherwise bind very promiscuously. Beyond
caging of the methyllysine, the mechanism of recognition of surrounding residues
varies among readers [19].
Like methyllysine, methylated arginine occupies an aromatic cage at the top of
the β-barrel structure of a Tudor domain. However, this cage is much narrower
than the cage for methyllysine and thus favors the planar guanidinium group [19].
Interestingly, the other structurally related members of the Royal superfamily,
namely, chromodomain, chromo-barrel, MBT, PWWP, and TTD modules, which
also feature the characteristic β-barrel topology, are not able to bind methylated
arginine [8, 19].
3 PHD Fingers
3.1 PHD Structure and Function
The plant homeodomain (PHD) finger was discovered in the Arabidopsis
protein HAT3.1 in 1993 [23] and has since been found in a variety of proteins
implicated in the regulation of chromatin structure and dynamics. The PHD finger
is an evolutionarily conserved zinc fingerlike motif which is present either as a
single module or in multiple copies in 291 human proteins [24], and, therefore, it is
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G. Sbardella
largest and most diverse set of readers. This includes plant homeodomains (PHDs),
WD-40 domains, chromatin organization modifier domains (chromodomains, CDs),
double chromodomains (DCDs), chromo-barrel domains, ADD (ATRX-DNMT3DNMT3L) domains, ankyrin repeats (ANKs), proline-tryptophan-tryptophanproline (PWWP) domains, bromo adjacent homology (BAH) domains, chromo-barrel,
chromodomain (CD), double chromodomain (DCD), HEAT, malignant brain tumor
(MBT) domains, SAWADEE, Tudor domains, tandem Tudor domain (TTD), and zinc
finger CW (zf-CW) domains [4, 8, 19–21]. Some methyllysine readers, including PHD
and zf-CW, show a high degree of sequence specificity, while others, including MBT
and WD40, are more promiscuous though they can select for a certain methylation
state of a target lysine (Fig. 2). Despite the wide variety of the readers and histone
targets, the majority of these domains have comparable binding affinities, with dissociation constants of the complexes being in the high nanomolar to the low micromolar
range [19, 22].
On the other hand, the only protein domain family currently known to bind
methylated arginine motifs is the Tudor family (although individual PHD and
WD40 domains also harbor this ability) [8, 19].
The main feature of all methyllysine-binding domains identified so far is that
they bind this PTM through an aromatic cage, typically formed by two to four
aromatic residues. The exact composition and size of the pocket are responsible for
the selectivity for mono-, di-, or trimethylated state of lysine [19]. Specificity for a
particular methylated lysine is imparted by interaction with surrounding residues.
Some histone readers show high degrees of specificity, whereas others are selective
for only a certain methylation state and otherwise bind very promiscuously. Beyond
caging of the methyllysine, the mechanism of recognition of surrounding residues
varies among readers [19].
Like methyllysine, methylated arginine occupies an aromatic cage at the top of
the β-barrel structure of a Tudor domain. However, this cage is much narrower
than the cage for methyllysine and thus favors the planar guanidinium group [19].
Interestingly, the other structurally related members of the Royal superfamily,
namely, chromodomain, chromo-barrel, MBT, PWWP, and TTD modules, which
also feature the characteristic β-barrel topology, are not able to bind methylated
arginine [8, 19].
3 PHD Fingers
3.1 PHD Structure and Function
The plant homeodomain (PHD) finger was discovered in the Arabidopsis
protein HAT3.1 in 1993 [23] and has since been found in a variety of proteins
implicated in the regulation of chromatin structure and dynamics. The PHD finger
is an evolutionarily conserved zinc fingerlike motif which is present either as a
single module or in multiple copies in 291 human proteins [24], and, therefore, it is
342
G. Sbardella