4 │ Histone H1 subtypes characteristics inferred from
protein-protein interactions
The notion that histone H1 act in the complexes with proteins has been
earlier confirmed by in vivo and in vitro experiments on
over a dozen examples, including mainly interactions involved in the
dynamic changes of chromatin states. 55 However, the
subsequent investigation performed on the proteome-scale revealed almost
two hundred of proteins which may bind to the histone H1. Analyses
conducted by Kalashnikova et al. 56 and Szerlong et
al. 57 indicate that histone H1 is essential for
organize the nucleolus protein network needed, among others, for RNA
splicing and ribosome biogenesis. These are the first studies
documenting such a wide range of possible histone H1 interactions
relating, however, only to two histone H1 variants purified from
cultured cells. Considering that the human H1 histones display a highest
degree of heterogeneity manifested by a presence of 11 variants58, a complete picture of H1 interactions remained
unknown. This work helps in determination of a scale in which histones
H1 might be active, simultaneously indicating on the mechanisms of their
operation. Because the computational analysis include effective methods
for prediction a biological significance of protein-protein interactions59, the sequence-based and structure-based approaches
were adopted for study of the interactions between histone H1 subtypes
and partnering proteins.
A characteristic of histone H1 subtypes interacting proteins location
presented in this work indicate that they have no preferences for an
occurrence in the nucleolus, in contrast to the subtype H1.0 for which
175 nucleolar interacting partners were identified. 56The partners of subtypes H1.1 – H1.5 are mainly nuclear and cytosolic
proteins but in the lower proportions remaining also in the membrane and
mitochondrion. Thus, it can be predicted that the functions of subtypes
H1.1 – H1.5 are predominantly realized in these cellular compartments.
The obtained data regarding functions confirm a shared way of histone H1
subtypes action but simultaneously indicate on new aspects of their
individualization. A clarification of distinction between commonality
and specificity can be observed in the juxtaposition of H1 interacting
proteins features presented in the Figure 6. Based on the selected
criteria including molecular function, biological processes and the
networks properties, histone H1 subtypes can be categorized according to
tendency of similar and/or dissimilar activity. A frequently occurring
are the common features of subtypes H1.1 and H1.4 (first category) and
subtypes H1.3 and H1.5 (second category), sometimes also characteristic
of subtype H1.2 (third category). Due to this, an activity of the said
pairs of subtypes is peculiarly limited to the selected processes but,
on the other hand, it can be realized in a similar way. In contrast, the
subtype H1.2 repeatedly appearing together with a pair of H1.1, H1.4
and/or H1.3, H1.5 should be treated as more ubiquitous and, thus, more
capable of engagement in a broader range of the activity. This stay in
agreement with suggestion that histone H1 subtypes may share
functionally redundant roles in some of the biological processes but
also act specifically in the other ones. 25 However,
such a grouped activities of H1 subtypes determined in this work
deviates from those which are characteristic of the DNA-associated
processes in the chromatin. For example, the strength of binding to the
DNA is high in the case of subtype H1.3 and H1.4 and decreases to
intermediate for subtype H1.2 and H1.5 and to the low for subtype H1.1.60 Likewise, the strong chromatin binging characterize
subtypes H1.4 and H1.5, in contrast to intermediate binding by subtype
H1.3 and weak binding by subtype H1.1. 61 It seems
that histone H1 subtypes may manifest various types of activities in
distinct cellular processes, in dependence of the contacts with the DNA
and proteins. The identified disparities between histone H1 subtypes are
also reflected by their presence in the various networks coordinating a
run of critical cell processes, i.e. ribosome biogenesis (subtype H1.1
and H1.4), cell cycle (subtype H1.3 and H1.5) and protein degradation
(subtype H1.2). However, the most important in this field is a function
of histone H1.3. As a hub protein, it play a central role in the
molecular organization of the network and is useful to highlight nodes
with special biological functions. 29 It seem that the
histone H1.3 may be considered as date (dynamic) hub. Due to a high
content of intrinsic structural disorder 51attributable mainly to the dynamic hubs 62, it can
bind its interaction partners in the times and/or location-specific
mode. 38
A type of histone H1 subtypes interactions, transient in term of the
stability and medium-strong in relation to the strength of binding, is
frequent in the biochemical pathways and regulatory networks and,
therefore, it might be considered as important in a range of cellular
functions. 2 Such a dynamic and reversible
interactions are typically accompanying with conformational changes of
proteins 63, so they are usually control by their
intrinsically disordered sequence stretches. 48 This
also applies to the histones H1 which may bind both disordered and
ordered proteins through a disordered interaction surface. In this
context, intrinsic disorder might be considered as prerequisite to
creation and maintenance of histone H1 interaction networks. However,
the mode of binding appropriate for histones H1 can be also influenced
by other stimuli, mainly by post-translational modifications52 attributable to the intrinsic disordered state.64 Because the modified residues, i.e. acetylated,
methylated and phosphorylated, were detected in the histones H1
disordered terminal domains 65, it can be assumed that
histone H1 subtypes interactions might be influenced by a cooperative
regulation of acetylation and methylation. 52