Evolution of an intricate J-protein network driving protein disaggregation in eukaryotes

  1. Nadinath B Nillegoda  Is a corresponding author
  2. Antonia Stank
  3. Duccio Malinverni
  4. Niels Alberts
  5. Anna Szlachcic
  6. Alessandro Barducci
  7. Paolo De Los Rios
  8. Rebecca C Wade  Is a corresponding author
  9. Bernd Bukau  Is a corresponding author
  1. University of Heidelberg, Germany
  2. Heidelberg Institute for Theoretical Studies, Germany
  3. École Polytechnique Fédérale de Lausanne, Switzerland
  4. Inserm, U1054, France
  5. University of Heidelberg, United Kingdom

Abstract

Hsp70 participates in a broad spectrum of protein folding processes extending from nascent chain folding to protein disaggregation. This versatility in function is achieved through a diverse family of J-protein cochaperones that select substrates for Hsp70. Substrate selection is further tuned by transient complexation between different classes of J-proteins, which expands the range of protein aggregates targeted by metazoan Hsp70 for disaggregation. We assessed the prevalence and evolutionary conservation of J-protein complexation and cooperation in disaggregation. We find the emergence of a eukaryote-specific signature for interclass complexation of canonical J-proteins. Consistently, complexes exist in yeast and human cells, but not in bacteria, and correlate with cooperative action in disaggregation in vitro. Signature alterations exclude some J-proteins from networking, which ensures correct J-protein pairing, functional network integrity and J-protein specialization. This fundamental change in J-protein biology during the prokaryote-to-eukaryote transition allows for increased fine-tuning and broadening of Hsp70 function in eukaryotes.

Article and author information

Author details

  1. Nadinath B Nillegoda

    Center for Molecular Biology, University of Heidelberg, Heidelberg, Germany
    For correspondence
    n.nillegoda@zmbh.uni-heidelberg.de
    Competing interests
    The authors declare that no competing interests exist.
  2. Antonia Stank

    Heidelberg Institute for Theoretical Studies, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Duccio Malinverni

    Laboratory of Statistical Biophysics, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  4. Niels Alberts

    Center for Molecular Biology, University of Heidelberg, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Anna Szlachcic

    Center for Molecular Biology, University of Heidelberg, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Alessandro Barducci

    Inserm, U1054, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1911-8039
  7. Paolo De Los Rios

    Laboratory of Statistical Biophysics, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  8. Rebecca C Wade

    Center for Molecular Biology, University of Heidelberg, Heidelberg, Germany
    For correspondence
    rebecca.wade@h-its.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5951-8670
  9. Bernd Bukau

    Center for Molecular Biology, University of Heidelberg, Heidelberg, United Kingdom
    For correspondence
    bukau@zmbh.uni-heidelberg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0521-7199

Funding

Deutsche Forschungsgemeinschaft (SFB1036 BU617/19-3)

  • Bernd Bukau

Alexander von Humboldt-Stiftung (NA)

  • Nadinath B Nillegoda

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2017, Nillegoda 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.

Metrics

  • 3,689
    views
  • 909
    downloads
  • 60
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Nadinath B Nillegoda
  2. Antonia Stank
  3. Duccio Malinverni
  4. Niels Alberts
  5. Anna Szlachcic
  6. Alessandro Barducci
  7. Paolo De Los Rios
  8. Rebecca C Wade
  9. Bernd Bukau
(2017)
Evolution of an intricate J-protein network driving protein disaggregation in eukaryotes
eLife 6:e24560.
https://doi.org/10.7554/eLife.24560

Share this article

https://doi.org/10.7554/eLife.24560

Further reading

    1. Biochemistry and Chemical Biology
    Shraddha KC, Kenny H Nguyen ... Thomas C Boothby
    Research Article

    The conformational ensemble and function of intrinsically disordered proteins (IDPs) are sensitive to their solution environment. The inherent malleability of disordered proteins, combined with the exposure of their residues, accounts for this sensitivity. One context in which IDPs play important roles that are concomitant with massive changes to the intracellular environment is during desiccation (extreme drying). The ability of organisms to survive desiccation has long been linked to the accumulation of high levels of cosolutes such as trehalose or sucrose as well as the enrichment of IDPs, such as late embryogenesis abundant (LEA) proteins or cytoplasmic abundant heat-soluble (CAHS) proteins. Despite knowing that IDPs play important roles and are co-enriched alongside endogenous, species-specific cosolutes during desiccation, little is known mechanistically about how IDP-cosolute interactions influence desiccation tolerance. Here, we test the notion that the protective function of desiccation-related IDPs is enhanced through conformational changes induced by endogenous cosolutes. We find that desiccation-related IDPs derived from four different organisms spanning two LEA protein families and the CAHS protein family synergize best with endogenous cosolutes during drying to promote desiccation protection. Yet the structural parameters of protective IDPs do not correlate with synergy for either CAHS or LEA proteins. We further demonstrate that for CAHS, but not LEA proteins, synergy is related to self-assembly and the formation of a gel. Our results suggest that functional synergy between IDPs and endogenous cosolutes is a convergent desiccation protection strategy seen among different IDP families and organisms, yet the mechanisms underlying this synergy differ between IDP families.

    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics
    Jie Luo, Jeff Ranish
    Tools and Resources

    Dynamic conformational and structural changes in proteins and protein complexes play a central and ubiquitous role in the regulation of protein function, yet it is very challenging to study these changes, especially for large protein complexes, under physiological conditions. Here, we introduce a novel isobaric crosslinker, Qlinker, for studying conformational and structural changes in proteins and protein complexes using quantitative crosslinking mass spectrometry. Qlinkers are small and simple, amine-reactive molecules with an optimal extended distance of ~10 Å, which use MS2 reporter ions for relative quantification of Qlinker-modified peptides derived from different samples. We synthesized the 2-plex Q2linker and showed that the Q2linker can provide quantitative crosslinking data that pinpoints key conformational and structural changes in biosensors, binary and ternary complexes composed of the general transcription factors TBP, TFIIA, and TFIIB, and RNA polymerase II complexes.