Journal of Molecular Biology
Volume 432, Issue 9, 17 April 2020, Pages 2949-2972
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Review
Probing Surfaces in Dynamic Protein Interactions

https://doi.org/10.1016/j.jmb.2020.02.032Get rights and content
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Highlights

  • Protein surfaces play key roles in dynamic protein–protein interactions.

  • NMR-based solvent paramagnetic relaxation enhancements (sPRE) report on protein surface accessibility.

  • Experimental sPRE data can be obtained easily without protein modification.

  • A plethora of structural and dynamic information can be obtained for protein–protein interactions using sPREs.

Abstract

Proteins and their interactions control a plethora of biological functions and enable life. Protein–protein interactions can be highly dynamic, involve proteins with different degrees of “foldedness,” and are often regulated through an intricate network of post-translational modifications. Central parts of protein–protein networks are intrinsically disordered proteins (IDPs). IDPs act as regulatory interaction hubs, enabled by their flexible nature. They employ various modes of binding mechanisms, from folding upon ligand binding to formation of highly dynamic “fuzzy” protein–protein complexes. Mutations or perturbations in regulation of IDPs are hallmarks of many diseases. Protein surfaces play key roles in protein–protein interactions. However, protein surfaces and protein surface accessibility are difficult to study experimentally. NMR-based solvent paramagnetic relaxation enhancement (sPRE) can provide quantitative experimental information on protein surface accessibility, which can be further used to obtain distance information for structure determination, identification of interaction surfaces, conformational changes, and identification of low-populated transient structure and long-range contacts in IDPs and dynamic protein–protein interactions. In this review, we present and discuss state-of the art sPRE techniques and their applications to investigate structure and dynamics of IDPs and protein–protein interactions. Finally, we provide an outline for potential future applications of the sPRE approach in combination with complementary techniques and modeling, to study novel paradigms, such as liquid–liquid phase separation, regulation of IDPs and protein–protein interactions by post-translational modifications, and targeting of disordered proteins.

Abbreviations

c-Myc
cellular myelocytomatosis oncogene
EM
electron microscopy
Gd-DTPA-BMA
gadolinium-diethylenetriamine pentaacetic acid‐bismethylamide
eIF4E
eukaryotic initiation factor 4E
IDP
intrinsically disordered proteins
IDR
intrinsically disordered regions
LLPS
liquid–liquid phase separation
NAC
non-Abeta component
NOEs
nuclear Overhauser effect
PPIs
protein–protein interactions
PRE
paramagnetic relaxation enhancement
PTMs
post-translational modifications
RDCs
residual dipolar couplings
SERF1
a member of the modifier of aggregation-4/small EDRK-rich factor (MOAG-4/SERF) family
sPRE
solvent paramagnetic relaxation enhancement

Keywords

solvent paramagnetic relaxation enhancement
intrinsically disordered proteins
protein–protein interactions
fuzzy complexes
liquid–liquid phase separation

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