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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Arabidopsis / genetics
  • Arabidopsis / metabolism
  • Arabidopsis Proteins / chemistry*
  • Arabidopsis Proteins / genetics
  • Arabidopsis Proteins / metabolism
  • Binding Sites
  • Cell Cycle Proteins / chemistry*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cytoskeletal Proteins / chemistry*
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • Humans
  • Intrinsically Disordered Proteins / chemistry*
  • Intrinsically Disordered Proteins / genetics
  • Intrinsically Disordered Proteins / metabolism
  • Models, Molecular
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Folding
  • Protein Interaction Domains and Motifs
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Sin3 Histone Deacetylase and Corepressor Complex / chemistry*
  • Sin3 Histone Deacetylase and Corepressor Complex / genetics
  • Sin3 Histone Deacetylase and Corepressor Complex / metabolism
  • TATA-Binding Protein Associated Factors / chemistry*
  • TATA-Binding Protein Associated Factors / genetics
  • TATA-Binding Protein Associated Factors / metabolism
  • Transcription Factor TFIID / chemistry*
  • Transcription Factor TFIID / genetics
  • Transcription Factor TFIID / metabolism
  • Transcription Factors / chemistry*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription Factors, TFII / chemistry*
  • Transcription Factors, TFII / genetics
  • Transcription Factors, TFII / metabolism
  • p300-CBP Transcription Factors / chemistry*
  • p300-CBP Transcription Factors / genetics
  • p300-CBP Transcription Factors / metabolism

Substances

  • AT1G27720 protein, Arabidopsis
  • Arabidopsis Proteins
  • CNOT9 protein, human
  • Cell Cycle Proteins
  • Cytoskeletal Proteins
  • Intrinsically Disordered Proteins
  • TAF4 protein, human
  • TATA-Binding Protein Associated Factors
  • Transcription Factor TFIID
  • Transcription Factors
  • Transcription Factors, TFII
  • USH1C protein, human
  • p300-CBP Transcription Factors
  • Sin3 Histone Deacetylase and Corepressor Complex