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Structure. 2017 Feb 7;25(2):305-316. doi: 10.1016/j.str.2016.12.005. Epub 2017 Jan 12.

Structural Basis for the Interaction of a Human Small Heat Shock Protein with the 14-3-3 Universal Signaling Regulator.

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Laboratory of Structural Biochemistry of Proteins, A.N. Bach Institute of Biochemistry, Federal Research Center "Fundamentals of Biotechnology", Russian Academy of Sciences, 119071 Moscow, Russia. Electronic address:
Laboratory for Biocrystallography, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium.
Laboratory of Protein Conformational Polymorphism in Health and Disease, Engelhardt Institute of Molecular Biology, 119991 Moscow, Russia.
York Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5YW, UK.
Department of Biochemistry, School of Biology, Moscow State University, 119991 Moscow, Russia.
Laboratory for Biocrystallography, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium. Electronic address:


By interacting with hundreds of protein partners, 14-3-3 proteins coordinate vital cellular processes. Phosphorylation of the small heat shock protein, HSPB6, within its intrinsically disordered N-terminal domain activates its interaction with 14-3-3, ultimately triggering smooth muscle relaxation. After analyzing the binding of an HSPB6-derived phosphopeptide to 14-3-3 using isothermal calorimetry and X-ray crystallography, we have determined the crystal structure of the complete assembly consisting of the 14-3-3 dimer and full-length HSPB6 dimer and further characterized this complex in solution using fluorescence spectroscopy, small-angle X-ray scattering, and limited proteolysis. We show that selected intrinsically disordered regions of HSPB6 are transformed into well-defined conformations upon the interaction, whereby an unexpectedly asymmetric structure is formed. This structure provides the first atomic resolution snapshot of a human small HSP in functional state, explains how 14-3-3 proteins sequester their regulatory partners, and can inform the design of small-molecule interaction modifiers to be used as myorelaxants.


14-3-3 proteins; conformational change; crystal structure; intrinsically disordered regions; phosphopeptides; protein-protein interaction; regulatory complex; small heat shock proteins; small-angle X-ray scattering; smooth muscle relaxation

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