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