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

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

Author information

1
VIB-VUB Center for Structural Biology, Vlaams Instituut voor Biotechnologie, Pleinlaan 2, 1050 Brussels, Belgium; Structural Biology Brussels, Department of Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
2
Department of Computer Science, Purdue University, West Lafayette, IN 47907, USA.
3
Department of Computer Science, Purdue University, West Lafayette, IN 47907, USA; Department of Biological Sciences, Purdue University, Hockmeyer Structural Biology Building, 249 S. Martin Jischke Dr West Lafayette, IN 47907, USA.
4
VIB-VUB Center for Structural Biology, Vlaams Instituut voor Biotechnologie, Pleinlaan 2, 1050 Brussels, Belgium; Structural Biology Brussels, Department of Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium; Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudosok korutja 2, 1117 Budapest, Hungary.
5
VIB-VUB Center for Structural Biology, Vlaams Instituut voor Biotechnologie, Pleinlaan 2, 1050 Brussels, Belgium. Electronic address: shoshana.wodak@vub.vib.be.

Abstract

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

PMID:
30878482
PMCID:
PMC6453724
[Available on 2020-04-05]
DOI:
10.1016/j.jmb.2019.03.008
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