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Proc Natl Acad Sci U S A. 2017 Dec 19;114(51):13453-13458. doi: 10.1073/pnas.1711543114. Epub 2017 Dec 5.

Conserved salt-bridge competition triggered by phosphorylation regulates the protein interactome.

Author information

1
Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637.
2
Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637.
3
Toyota Technological Institute at Chicago, Chicago, IL 60637.
4
Department of Genetics, University of Chicago, Chicago, IL 60637.
5
Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455.
6
Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, 97078 Würzburg, Germany.
7
Institute of Pharmacology and Toxicology, University of Würzburg, 97078 Würzburg, Germany.
8
Cardiovascular Pharmacology, Leibniz-Institut für Analytische Wissenschaften (ISAS), 44139 Dortmund, Germany.
9
West German Heart and Vascular Center Essen, University Hospital Essen, 45122 Essen, Germany.
10
Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637; trsosnic@uchicago.edu m-rosner@uchicago.edu.
11
Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637; trsosnic@uchicago.edu m-rosner@uchicago.edu.

Abstract

Phosphorylation is a major regulator of protein interactions; however, the mechanisms by which regulation occurs are not well understood. Here we identify a salt-bridge competition or "theft" mechanism that enables a phospho-triggered swap of protein partners by Raf Kinase Inhibitory Protein (RKIP). RKIP transitions from inhibiting Raf-1 to inhibiting G-protein-coupled receptor kinase 2 upon phosphorylation, thereby bridging MAP kinase and G-Protein-Coupled Receptor signaling. NMR and crystallography indicate that a phosphoserine, but not a phosphomimetic, competes for a lysine from a preexisting salt bridge, initiating a partial unfolding event and promoting new protein interactions. Structural elements underlying the theft occurred early in evolution and are found in 10% of homo-oligomers and 30% of hetero-oligomers including Bax, Troponin C, and Early Endosome Antigen 1. In contrast to a direct recognition of phosphorylated residues by binding partners, the salt-bridge theft mechanism represents a facile strategy for promoting or disrupting protein interactions using solvent-accessible residues, and it can provide additional specificity at protein interfaces through local unfolding or conformational change.

KEYWORDS:

Raf Kinase Inhibitory Protein; conformational change; phospho-swap; protein interaction; salt-bridge competition

PMID:
29208709
PMCID:
PMC5754776
DOI:
10.1073/pnas.1711543114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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