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Review
. 2021 Jan-Jun:296:100226.
doi: 10.1074/jbc.REV120.012928. Epub 2020 Dec 29.

αα-Hub domains and intrinsically disordered proteins: A decisive combo

Katrine Bugge  1 , Lasse Staby  1 , Edoardo Salladini  2 , Rasmus G Falbe-Hansen  2 , Birthe B Kragelund  3 , Karen Skriver  4
Affiliations
Review

αα-Hub domains and intrinsically disordered proteins: A decisive combo

Katrine Bugge et al. J Biol Chem. 2021 Jan-Jun.

Abstract

Hub proteins are central nodes in protein-protein interaction networks with critical importance to all living organisms. Recently, a new group of folded hub domains, the αα-hubs, was defined based on a shared αα-hairpin supersecondary structural foundation. The members PAH, RST, TAFH, NCBD, and HHD are found in large proteins such as Sin3, RCD1, TAF4, CBP, and harmonin, which organize disordered transcriptional regulators and membrane scaffolds in interactomes of importance to human diseases and plant quality. In this review, studies of structures, functions, and complexes across the αα-hubs are described and compared to provide a unified description of the group. This analysis expands the associated molecular concepts of "one domain-one binding site", motif-based ligand binding, and coupled folding and binding of intrinsically disordered ligands to additional concepts of importance to signal fidelity. These include context, motif reversibility, multivalency, complex heterogeneity, synergistic αα-hub:ligand folding, accessory binding sites, and supramodules. We propose that these multifaceted protein-protein interaction properties are made possible by the characteristics of the αα-hub fold, including supersite properties, dynamics, variable topologies, accessory helices, and malleability and abetted by adaptability of the disordered ligands. Critically, these features provide additional filters for specificity. With the presentations of new concepts, this review opens for new research questions addressing properties across the group, which are driven from concepts discovered in studies of the individual members. Combined, the members of the αα-hubs are ideal models for deconvoluting signal fidelity maintained by folded hubs and their interactions with intrinsically disordered ligands.

Keywords: IDP; SLiM; context; dynamics; hub; ligand binding; signaling; transcription.

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Conflict of interest statement

Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.

Figures

Figure 1
Figure 1
Structures and evolution of αα-hub domains.A–E, representative structures of the current αα-hub subgroups PAH (2rmr), RST (5n9q), TAFH (2pp4), NCBD (2kkj), and HHD (4fqn), respectively. For each domain, the helices are color coded with H1 (orange), H2 (blue), H3 (green), H4 (red), and H5 (pink). For the domains containing the αL-β4 loop, the hydrophobic β3-position is shown as gray sticks. Sequence logos below each domain illustrate the conservation of the H2-H3 loop region across phylogenetically representative species with each position named according to the αL-β4 loop nomenclature. In the structures of HHD the β2-residue (marked with an asterisk) is located in the site normally occupied by the β3-residue in the αL-β4 (see also Fig. S1C). Empty positions indicate either lack of conservation (for RST) or the presence of a gap in the alignment (HHD). F, compositional features of the prototypical αα-hub. Side and front views illustrate the different surfaces, helices, and loops as defined in this review. Zoom shows the configuration of the αL-β4 loop with the hydrophobic β3-position forming stabilizing interactions with side chains from H2 and H3. G, evolutionary proliferation of αα-hubs and relationships between major eukaryotic groups (159). Branch lengths are arbitrary. Blue, PAH; green, RST; red, TAFH; orange, NCBD; purple, HHD.
Figure 2
Figure 2
αα-Hub protein domain structures. αα-hub domain structures present in proteins with known functions or appearing more than 10 times in InterPro. The αα-hub domains included are: A, PAH, B, RST, C, TAF4, D, NCBD, E, HHD. The GO terms associated with the different αα-hub proteins are shown to the right. The schematics are not drawn to scale, the relative distance between the domains vary, and some of the proteins have more than one copy of the domains shown. GO, gene ontology.
Figure 3
Figure 3
αα-Hub protein interactions. Examples of protein complexes and interactions of αα-hub proteins, focusing mainly on the interactions of the αα-hub domains. A, Sin3 as part of a coregulator complex. TFs, coregulators, adapters, and enzymes are shown bound to or as part of the binding pool of their target domains in Sin3. The classic functional role of Sin3 as a scaffold for chromatin remodeling is also shown. B, RCD1 in regulation of biotic and abiotic stress responses. The interactions mediate suppression of plant immunity (through HaRxL) and coordination of communication between ROS signals emitted from mitochondria and chloroplasts (through ANAC013 and ANAC017). C, TAF4 as part of the RNA Pol II preinitiation complex. TFs binding to the TAFH domain and implicated in embryonic pattering, and programmed cell death are shown. D, CBP/p300 is a central node in eukaryotic regulatory networks regulating TFs and chromatin via their histone acetyl transferase activity. The TAZ, KIX, and NCBD domains are scaffolds for interactions with IDRs of proteins shown with names for only NCBD ligands. E, Harmonin anchored interactions in regulation of hearing and vision. Cad23 assembles the upper part of the tip link, and its cytoplasmic tail is anchored to the actin filament of stereocilia via binding to harmonin.
Figure 4
Figure 4
Alignments of sequences of PAH1, PAH2, and RST, respectively, from phylogenetically representative species and comparison with 3D structures. Sequences were aligned with Clustal Omega and visualized in Jalview. Available 3D structures of each subgroup were manually inspected and compared with the conservation alignment, and residues with identity >50% that could not be readily explained by fold-conservation (no tertiary side chain contacts) were highlighted in red (alignments and structures). The fold-defining positions (identity above 50% and tertiary side chain contacts) were colored blue in accordance with percentage identity (darker is higher identity, alignments, and structures). Above each alignment, the β3-position is highlighted with “∗,” and the gray boxes indicate the helix boundaries in the free (light gray) and complexed (darker gray, variations are different structures) αα-hubs. Species are given as four-letter abbreviations, with full names given in Table S2. A, PAH1. Protein Data Bank (PDB) codes 2czy, 2rms. The peptides of the ligands REST (2czy) and SAP25 (2rms) are shown semitransparent in orange variations. B, PAH2. PDB codes 1s5r, 1e91, 1g1e. The peptides of the ligands HBP1 (1s5r) and Mad1 (1e91, 1g1e) are shown semitransparent in orange variations. C, RST. PDB codes 5oao, 5oap. The ligand peptide of DREB2a (5oap) is shown semitransparent in yellow as an ensemble of 10 lowest-energy structures.
Figure 5
Figure 5
The modus operandi of αα-hubs.A, the αα-hub-binding region of free protein ligand may fluctuate between hairpins, helices, and bent structures as in the case of the Sin3b-PAH1-binding SLiM of REST (107). B, protein ligand using a SLiM with hydrophobic and acidic residues for αα-hub binding as in the Sin3-PAH2-binding SLiM of Mad1 (108). The SLiM is often part of a larger intrinsically disordered context. C, protein ligands may use SLiM reversibility for governing specificity as in the case of Sap25 and REST binding to Sin3-PAH1 (Protein Data Bank [PDB] codes 1s5q and 1s5r) (44). D, ligands using coupled folding and binding, through conformational selection and/or induced fit, as in the case of ACTR association with NCBD (based on PDB codes 2kkj and 1kbh) (132). E, αα-Hub:ligand complexes may retain some disorder as in the case of the Sin3a-PAH1:SAP25 complex (PDB code 2rms) (103). F, structural heterogeneity in an αα-hub:ligand complex as in the case of RCD1-RST complexes with NAC and DREB2a transcription factors (PDB codes 5oao and 5oap) (21, 36, 58). G, αα-hub domains may fold synergistically with a disordered protein ligand to form different bound ligand structures as in the case of NCBD complexes with Src1 (left) and ACTR (right), respectively (PDB codes 2c52 and 1kbh) (121). H, allosteric effects of the SLiM context on ligand association with αα-hubs as in the case of RCD1-RST association with ANAC013 (58). I, αα-hubs may be part of supramodules as in the case of the harmonin:sans complex (PDB code 3k1r) (48).
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References

    1. Oldfield C.J., Meng J., Yang J.Y., Yang M.Q., Uversky V.N., Dunker A.K. Flexible nets: disorder and induced fit in the associations of p53 and 14-3-3 with their partners. BMC Genomics. 2008;9 Suppl 1 - PMC - PubMed
    1. Cumberworth A., Lamour G., Babu M.M., Gsponer J. Promiscuity as a functional trait: intrinsically disordered regions as central players of interactomes. Biochem. J. 2013;454:361–369. - PubMed
    1. Patil A., Kinoshita K., Nakamura H. Hub promiscuity in protein-protein interaction networks. Int. J. Mol. Sci. 2010;11:1930–1943. - PMC - PubMed
    1. Han J.J., Bertin N., Hao T., Goldberg D.S., Berriz G.F., Zhang L.V., Dupuy D., Walhout A.J.M., Cusick M.E., Roth F.P., Vidal M. Evidence for dynamically organized modularity in the yeast protein-protein interaction network. Nature. 2004;430:88–93. - PubMed
    1. Hu G., Wu Z., Uversky V.N., Kurgan L. Functional analysis of human hub proteins and their interactors involved in the intrinsic disorder-enriched interactions. Int. J. Mol. Sci. 2017;18:2761. - PMC - PubMed

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