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J Am Chem Soc. 2018 Jan 24;140(3):1148-1158. doi: 10.1021/jacs.7b12407. Epub 2018 Jan 11.

Deciphering the Dynamic Interaction Profile of an Intrinsically Disordered Protein by NMR Exchange Spectroscopy.

Author information

1
Université Grenoble Alpes, CNRS, CEA, IBS , F-38000 Grenoble, France.
2
Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes , F-38000 Grenoble, France.
3
Laboratoire des Biomolécules, Département de Chimie, École Normale Supérieur, UPMC Université Paris 06, CNRS, PSL Research University , 24 rue Lhomond, 75005 Paris, France.
4
Sorbonne Universités, UPMC Université Paris 06 , École Normale Supérieur, CNRS, Laboratoire des Biomolécules (LBM), 75005 Paris, France.

Abstract

Intrinsically disordered proteins (IDPs) display a large number of interaction modes including folding-upon-binding, binding without major structural transitions, or binding through highly dynamic, so-called fuzzy, complexes. The vast majority of experimental information about IDP binding modes have been inferred from crystal structures of proteins in complex with short peptides of IDPs. However, crystal structures provide a mainly static view of the complexes and do not give information about the conformational dynamics experienced by the IDP in the bound state. Knowledge of the dynamics of IDP complexes is of fundamental importance to understand how IDPs engage in highly specific interactions without concomitantly high binding affinity. Here, we combine rotating-frame R, Carr-Purcell-Meiboom Gill relaxation dispersion as well as chemical exchange saturation transfer to decipher the dynamic interaction profile of an IDP in complex with its partner. We apply the approach to the dynamic signaling complex formed between the mitogen-activated protein kinase (MAPK) p38α and the intrinsically disordered regulatory domain of the MAPK kinase MKK4. Our study demonstrates that MKK4 employs a subtle combination of interaction modes in order to bind to p38α, leading to a complex displaying significantly different dynamics across the bound regions.

PMID:
29276882
DOI:
10.1021/jacs.7b12407
[Indexed for MEDLINE]

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