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Structural basis for the interaction of a human small heat shock protein with the 14-3-3 universal signaling regulator

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Author(s)

  • Nikolai N Sluchanko
  • Steven Beelen
  • Alexandra A Kulikova
  • Stephen D Weeks
  • Alfred A Antson
  • Nikolai B Gusev
  • Sergei V Strelkov

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Publication details

JournalStructure
DateAccepted/In press - 12 Dec 2016
DateE-pub ahead of print - 12 Jan 2017
DatePublished (current) - 7 Feb 2017
Issue number2
Volume25
Number of pages12
Pages (from-to)305–316
Early online date12/01/17
Original languageEnglish

Abstract

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.

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© 2017 Elsevier B.V. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

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