domain contains a five-stranded antiparallel β-barrel core followed by a helix bundle
of one to six α-helixes following the β-barrel [185]. The PWWP motif (SWWP
in DNMT3B) belongs to the β-barrel and is at the interface between the two
subdomains. The WWP submotif initiates strand β2. While the PWWP domain
of DNMT3B binds DNA, there is evidence that it also interacts with methylated
targets, and for several other proteins, it was demonstrated that the PWWP domain
is a methyllysine-binding domain [124, 184, 186–188]. General principles for the
PWWP fold were derived from the structural characterization of seven human
proteins that recognize a methylated lysine [184]. The PWWP domains can be
subdivided into three units, namely, a β-barrel, an insertion motif between the second
and third strand of the β-barrel which varies in length and secondary structure, and
a C-terminal α-helical bundle. WHSC1 is a member of the NSD (nuclear receptor
SET domain-containing) family of proteins, large multidomain-containing proteins
that, in addition to the PWWP domain, include PHD domains and a catalytic SET
(Su(var), E(z), and Trithorax) histone methyltransferase domain [189]. Upregulation
of WHSC1 has been linked to several cancers including neuroblastoma [190],
gliomas [191], and several others including bladder cancer [190] and has also been
linked to increased tumor aggressiveness [192].
Furthermore, a gain-of-function WHSC1 point mutation (E1099K) has also
been identified in pediatric acute lymphoblastic leukemia cell lines resulting in a
dependency on mutant WHSC1 activity [193]. Amplification of WHSC1L1 has been
seen in breast cancer where knockdown modulated the growth and survival of these
cells [194]. Interestingly, while no small molecules have been developed to date
to target the PWWP domain as a methyllysine reader, very recently a peptide
inhibitor targeting the SET domain of WHSC1 has been reported [195].
5 The WD40 Repeat Domain
Proteins that contain WD40 domains constitute a large family, and examples have
been identified in roles throughout the cell [196]. In the nucleus, WD40 β-propeller
proteins are frequently found as components of chromatin-associated complexes.
Here, they mediate inter-complex interactions or facilitate tethering of the complexes
to the nucleosome. WD40 repeat proteins are commonly part of large, multiprotein
complexes whose protein-protein interactions help orchestrate an array of downstream effects such as vesicle biogenesis [197], cytokinesis [198], chromatin dynamics (i.e., DNA replication and cell cycle progression) [199], and transcriptional
regulation [200–203]. More than one WD40 domain protein may be found in
a single complex. As yet, a high-resolution structure of a complex including a
β-propeller domain, showing its full set of interactions, is not available. Nevertheless, a number of pair-wise interactions between the WD40 proteins and histone
proteins, or peptides mimicking histones, have been characterized. These, rather
than displaying a common theme, illustrate the versatility of the WD40 β-propeller
fold [204].
372
G. Sbardella
of one to six α-helixes following the β-barrel [185]. The PWWP motif (SWWP
in DNMT3B) belongs to the β-barrel and is at the interface between the two
subdomains. The WWP submotif initiates strand β2. While the PWWP domain
of DNMT3B binds DNA, there is evidence that it also interacts with methylated
targets, and for several other proteins, it was demonstrated that the PWWP domain
is a methyllysine-binding domain [124, 184, 186–188]. General principles for the
PWWP fold were derived from the structural characterization of seven human
proteins that recognize a methylated lysine [184]. The PWWP domains can be
subdivided into three units, namely, a β-barrel, an insertion motif between the second
and third strand of the β-barrel which varies in length and secondary structure, and
a C-terminal α-helical bundle. WHSC1 is a member of the NSD (nuclear receptor
SET domain-containing) family of proteins, large multidomain-containing proteins
that, in addition to the PWWP domain, include PHD domains and a catalytic SET
(Su(var), E(z), and Trithorax) histone methyltransferase domain [189]. Upregulation
of WHSC1 has been linked to several cancers including neuroblastoma [190],
gliomas [191], and several others including bladder cancer [190] and has also been
linked to increased tumor aggressiveness [192].
Furthermore, a gain-of-function WHSC1 point mutation (E1099K) has also
been identified in pediatric acute lymphoblastic leukemia cell lines resulting in a
dependency on mutant WHSC1 activity [193]. Amplification of WHSC1L1 has been
seen in breast cancer where knockdown modulated the growth and survival of these
cells [194]. Interestingly, while no small molecules have been developed to date
to target the PWWP domain as a methyllysine reader, very recently a peptide
inhibitor targeting the SET domain of WHSC1 has been reported [195].
5 The WD40 Repeat Domain
Proteins that contain WD40 domains constitute a large family, and examples have
been identified in roles throughout the cell [196]. In the nucleus, WD40 β-propeller
proteins are frequently found as components of chromatin-associated complexes.
Here, they mediate inter-complex interactions or facilitate tethering of the complexes
to the nucleosome. WD40 repeat proteins are commonly part of large, multiprotein
complexes whose protein-protein interactions help orchestrate an array of downstream effects such as vesicle biogenesis [197], cytokinesis [198], chromatin dynamics (i.e., DNA replication and cell cycle progression) [199], and transcriptional
regulation [200–203]. More than one WD40 domain protein may be found in
a single complex. As yet, a high-resolution structure of a complex including a
β-propeller domain, showing its full set of interactions, is not available. Nevertheless, a number of pair-wise interactions between the WD40 proteins and histone
proteins, or peptides mimicking histones, have been characterized. These, rather
than displaying a common theme, illustrate the versatility of the WD40 β-propeller
fold [204].
372
G. Sbardella