1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics
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A conserved histidine modulates HSPB5 structure to trigger chaperone activity in response to stress-related acidosis

  1. Ponni Rajagopal
  2. Eric Tse
  3. Andrew J Borst
  4. Scott P Delbecq
  5. Lei Shi
  6. Daniel P Southworth
  7. Rachel E Klevit  Is a corresponding author
  1. University of Washington, United Kingdom
  2. University of Michigan, United States
  3. University of Washington, United States
Research Article
  • Cited 31
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Cite this article as: eLife 2015;4:e07304 doi: 10.7554/eLife.07304

Abstract

Small heat shock proteins (sHSPs) are essential 'holdase' chaperones that form large assemblies and respond dynamically to pH and temperature stresses to protect client proteins from aggregation. While the alpha-crystallin domain (ACD) dimer of sHSPs is the universal building block, how the ACD transmits structural changes in response to stress to promote holdase activity is unknown. We found that the dimer interface of HSPB5 is destabilized over physiological pHs and a conserved histidine (His-104) controls interface stability and oligomer structure in response to acidosis. Destabilization by pH or His-104 mutation shifts the ACD from dimer to monomer but also results in a large expansion of HSPB5 oligomer states. Remarkably, His-104 mutant-destabilized oligomers are efficient holdases that reorganize into structurally distinct client-bound complexes. Our data support a model for sHSP function wherein cell stress triggers small perturbations that alter the ACD building blocks to unleash a cryptic mode of chaperone action.

Article and author information

Author details

  1. Ponni Rajagopal

    Department of Biochemistry, University of Washington, Seattle, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Eric Tse

    Department of Biological Chemistry, Life Sciences Institute, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Andrew J Borst

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Scott P Delbecq

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Lei Shi

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Daniel P Southworth

    Department of Biological Chemistry, Life Sciences Institute, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Rachel E Klevit

    Department of Biochemistry, University of Washington, Seattle, United States
    For correspondence
    klevit@u.washington.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Volker Dötsch, Goethe University, Germany

Publication history

  1. Received: March 3, 2015
  2. Accepted: May 8, 2015
  3. Accepted Manuscript published: May 11, 2015 (version 1)
  4. Version of Record published: June 5, 2015 (version 2)

Copyright

© 2015, Rajagopal et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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