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PreprintCited by 39Heat shock proteins researchGenomics and Phylogenetic StudiesMachine Learning in Bioinformatics

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Data-driven large-scale genomic analysis reveals an intricate phylogenetic and functional landscape in J-domain proteins

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Malinverni, Duccio, Zamuner, Stefano, Rebeaud, Mathieu E., Barducci, Alessandro, Nillegoda, Nadinath B., De Los Rios, Paolo·2022·Proceedings of the National Academy of Sciences
DOI 10.1101/2022.02.28.482344PMC PMC10410713

Preprint — published as 10.1073/pnas.2218217120 · Paper page

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Abstract

The 70 kDalton Heat shock protein (Hsp70) chaperone system is emerging as a central hub of the proteostasis network that helps maintain protein homeostasis in all organisms. The recruitment of Hsp70 to perform a vast array of different cellular functions is regulated by a family of co-chaperones known as J-domain proteins (JDP) that bear a small namesake J-domain, which is required to interact and drive the ATPase cycle of Hsp70s. Both prokaryotic and eukaryotic JDPs display staggering diversity in domain architecture (besides the ubiquitous J-domain), function, and cell localization. On the contrary, a relatively small number of Hsp70 paralogs exist in cells, suggesting a high degree of specificity, but also promiscuity, in the partnering between JDPs and Hsp70s. Very little is known about the JDP family, despite their essential role in cellular proteostasis, development, and the link to a broad range of human diseases. The number of JDP gene sequences identified across all kingdoms as a consequence of advancements in sequencing technology has exponentially increased, where it is now beyond the ability of careful manual curation. In this work, we first provide a broad overview of the JDP repertoire accessible from public databases, and then we use an automated classification scheme, based on Artificial Neural Networks (ANNs), to demonstrate that the sequences of J-domains carry sufficient discriminatory information to recover with high reliability the phylogeny, localization, and domain composition of the corresponding full-length JDP. By harnessing the interpretability of the ANNs, we find that many of the discriminatory sequence positions match to residues that form the interaction interface between the J-domain and Hsp70. This reveals that key residues within the J-domains have coevolved with their obligatory Hsp70 partners to build chaperone circuits for specific functions in cells.

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Metadata

Authors
Malinverni, D., Zamuner, S., Rebeaud, M. E., Barducci, A., Nillegoda, N. B., & De Los Rios, P.
Affiliations
  • St. Jude Children's Research Hospital (US)
  • École Polytechnique Fédérale de Lausanne (CH)
  • Centre National de la Recherche Scientifique (FR)
  • Australian Regenerative Medicine Institute (AU)
Corresponding author
Nillegoda, Nadinath B.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
openRxiv
Published
2022-03-02
Volume
120
Issue
32
Pages
e2218217120-e2218217120
ISSN
0027-8424 (ISSN-L)
DOI
10.1101/2022.02.28.482344
PMC
PMC10410713
OpenAlex
W4385409825
Cited by
39
References
1
Citations by year
2026: 6 · 2025: 13 · 2024: 13 · 2023: 6 · 2022: 1
FWCI
1.00
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by-nc-nd)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
Funders
  • National Science Foundation
  • Australian Government
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (181910, 163042)
  • Monash University
  • Department of Health and Aged Care, Australian Government (APP1197021)
  • State Government of Victoria
  • Medical Research Council
  • National Health and Medical Research Council (1197021)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Machine Learning in Bioinformatics
Keywords
Hsp40, Hsp70 chaperones, Hsp70 co-chaperone, proteostasis, phylogenetic classification, domain architecture, subcellular localization, coevolution, artificial neural networks, sequence classification
MeSH terms
Amino Acid Sequence, Humans, Phylogeny, Molecular Chaperones, HSP70 Heat-Shock Proteins, Genomics, HSP40 Heat-Shock Proteins

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