Background: Signal fidelity depends on protein-protein interaction-'hubs' integrating cues from large interactomes. Recently, and based on a common secondary structure motif, the alpha alpha-hubs were defined, which are small alpha-helical domains of large, modular proteins binding intrinsically disordered transcriptional regulators.

Methods: Comparative structural biology.

Results: We assign the harmonin-homology-domain (HHD, also named the harmonin N-terminal domain, NTD) present in large proteins such as harmonin, whirlin, cerebral cavernous malformation 2, and regulator of telomere elongation 1 to the alpha alpha-hubs. The new member of the alpha alpha-hubs expands functionality to include scaffolding of supra-modular complexes mediating sensory perception, neurovascular integrity and telomere regulation, and reveal novel features of the alpha alpha-hubs. As a common trait, the alpha alpha-hubs bind intrinsically disordered ligands of similar properties integrating similar cellular cues, but without cross-talk.

Conclusion: The inclusion of the HHD in the alpha alpha-hubs has uncovered new features, exemplifying the utility of identifying groups of hub domains, whereby discoveries in one member may cross-fertilize discoveries in others. These features make the alpha alpha-hubs unique models for decomposing signal specificity and fidelity. Using these as models, together with other suitable hub domain, we may advance the functional understanding of hub proteins and their role in cellular communication and signaling, as well as the role of intrinsically disordered proteins in signaling networks.