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

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.

Dilute phase oligomerization can oppose phase separation and modulate material properties of a ribonucleoprotein condensate

“…It is well known that many IDRs undergo coupled binding and folding reactions either through heterotypic interactions with cognate binding partners or via homotypic interactions that lead to dimers and higher-order oligomers (41)(42)(43)(44)(45). An archetypal example of dimerization induced folding of an IDR is the leucine zipper motif, which has a weak intrinsic preference for alphahelical conformations and forms coiled-coil alpha-helices as dimers (45,46) or higher-order oligomers (47).…”

Dilute phase oligomerization can oppose phase separation and modulate material properties of a ribonucleoprotein condensate

“…It is well known that many IDRs undergo coupled binding and folding reactions either through heterotypic interactions with cognate binding partners or via homotypic interactions that lead to dimers and higher-order oligomers ( 41 – 45 ). An archetypal example of dimerization-induced folding of an IDR is the leucine zipper motif, which has a weak intrinsic preference for alpha-helical conformations and forms coiled-coil alpha-helical dimers ( 45 , 46 ) or higher-order oligomers ( 47 ).…”

αα-hub coregulator structure and flexibility determine transcription factor binding and selection in regulatory interactomes

“…Thus, despite intensive studies for more than 30 years ( 7 , 10 , 12 ), TF–coregulator specificity remains enigmatic, and additional model systems are needed. One recently established model system is constituted by the αα-hub–TF interactions ( 13 , 14 ). In this model system, topologically similar, evolutionary unrelated, αα-hub domains found throughout eukaryotes interact with numerous unrelated intrinsically disordered TFs using diverse molecular features.…”

“…The αα-hubs were recently defined based on structural and functional similarities of RST (radical-induced cell death1 [RCD1], similar to RCD one [SRO], and transcription initiation factor TFIID-subunit [TAF4]), paired amphipathic helix, TATA-box–associated factor homology (TAFH), harmonin–homology domain, and nuclear coactivator–binding domain of the important transcriptional regulators RCD1, Sin3, TAF4, and CREB-binding protein ( 13 , 14 , 15 ). αα-hubs are small (<100 residues) α-helical domains present in larger multidomain proteins, and they share an αα-hairpin super secondary motif, linking variable, malleable helices of different lengths.…”

“…αα-hubs are small (<100 residues) α-helical domains present in larger multidomain proteins, and they share an αα-hairpin super secondary motif, linking variable, malleable helices of different lengths. The prototypical αα-hub domain consists of four α-helices, and its αα-hairpin is stabilized by a hydrophobic β3-loop residue ( 13 , 14 , 15 ). Most αα-hub–containing proteins organize large interactomes ( 8 , 13 , 16 , 17 ), with intrinsically disordered TFs being over-represented among αα-hub ligands ( 13 ) and thus typically act as coregulators of transcription.…”