The Balancing Act of Intrinsically Disordered Proteins: Enabling Functional Diversity while Minimizing Promiscuity

J Mol Biol. 2019 Apr 5;431(8):1650-1670. doi: 10.1016/j.jmb.2019.03.008. Epub 2019 Mar 13.


Intrinsically disordered proteins (IDPs) or regions (IDRs) perform diverse cellular functions, but are also prone to forming promiscuous and potentially deleterious interactions. We investigate the extent to which the properties of, and content in, IDRs have adapted to enable functional diversity while limiting interference from promiscuous interactions in the crowded cellular environment. Information on protein sequences, their predicted intrinsic disorder, and 3D structure contents is related to data on protein cellular concentrations, gene co-expression, and protein-protein interactions in the well-studied yeast Saccharomyces cerevisiae. Results reveal that both the protein IDR content and the frequency of "sticky" amino acids in IDRs (those more frequently involved in protein interfaces) decrease with increasing protein cellular concentration. This implies that the IDR content and the amino acid composition of IDRs experience negative selection as the protein concentration increases. In the S. cerevisiae protein-protein interaction network, the higher a protein's IDR content, the more frequently it interacts with IDR-containing partners, and the more functionally diverse the partners are. Employing a clustering analysis of Gene Ontology terms, we newly identify ~600 putative multifunctional proteins in S. cerevisiae. Strikingly, these proteins are enriched in IDRs and contribute significantly to all the observed trends. In particular, IDRs of multi-functional proteins feature more sticky amino acids than IDRs of their non-multifunctional counterparts, or the surfaces of structured yeast proteins. This property likely affords sufficient binding affinity for the functional interactions, commonly mediated by short IDR segments, thereby counterbalancing the loss in overall IDR conformational entropy upon binding.

Keywords: intrinsic structural disorder; multifunctional proteins; protein abundance; protein interaction network; yeast.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Intrinsically Disordered Proteins / chemistry
  • Intrinsically Disordered Proteins / metabolism*
  • Protein Conformation
  • Protein Interaction Maps*
  • Saccharomyces cerevisiae / chemistry
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / metabolism*


  • Intrinsically Disordered Proteins
  • Saccharomyces cerevisiae Proteins