TY - JOUR

T1 - Connecting the αα-hubs

T2 - same fold, disordered ligands, new functions

AU - Staby, Lasse

AU - Bugge, Katrine

AU - Falbe-Hansen, Rasmus Greve

AU - Salladini, Edoardo

AU - Skriver, Karen

AU - Kragelund, Birthe B.

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - Interactome

KW - Intrinsically disordered protein

KW - IDP

KW - NCBD

KW - PAH

KW - RST

KW - HHD

KW - Signaling

KW - TAFH

KW - Hub proteins

KW - INTRINSIC DISORDER

KW - SIN3 COREPRESSOR

KW - PROTEIN

KW - COMPLEX

KW - BINDING

KW - REVEALS

KW - DOMAIN

KW - PAH1

U2 - 10.1186/s12964-020-00686-8

DO - 10.1186/s12964-020-00686-8

M3 - Letter

C2 - 33407551

VL - 19

JO - Cell Communication and Signaling

JF - Cell Communication and Signaling

SN - 1478-811X

M1 - 2

ER -