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Mapping SP-C co-chaperone binding sites reveals molecular consequences of disease-causing mutations on protein maturation

Author

Listed:
  • Kristine F. R. Pobre-Piza

    (St. Jude Children’s Research Hospital)

  • Melissa J. Mann

    (St. Jude Children’s Research Hospital)

  • Ashley R. Flory

    (St. Jude Children’s Research Hospital)

  • Linda M. Hendershot

    (St. Jude Children’s Research Hospital)

Abstract

BiP co-chaperones ERdj4, ERdj5, and GRP170 associate in cells with peptides predicted to be aggregation prone. Here, extending these findings to a full-length protein, we examine two Interstitial Lung Disease-associated mutants (ILD) of surfactant protein C (SP-C). The TANGO algorithm, which identifies sequences prone to formation of β strand aggregates, found three such regions in SP-C: the N-terminal transmembrane (TM) domain and two sites in the intermolecular chaperone BRICHOS domain. We show the ILD mutants disrupt di-sulfide bond formation in the BRICHOS domain and expose the aggregation-prone peptides leading to binding of ERdj4, ERdj5, and GRP170. The destabilized mutant BRICHOS domain fails to properly insert its TM region in the ER membrane, exposing part of the N-terminal TM domain site. Our studies with ILD-associated mutant proteins provide insights into the specificity of ERdj4, ERdj5, and GRP170, identify context-dependent differences in their binding, and reveal molecular consequences of disease-associated mutants on folding.

Suggested Citation

  • Kristine F. R. Pobre-Piza & Melissa J. Mann & Ashley R. Flory & Linda M. Hendershot, 2022. "Mapping SP-C co-chaperone binding sites reveals molecular consequences of disease-causing mutations on protein maturation," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29478-z
    DOI: 10.1038/s41467-022-29478-z
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    References listed on IDEAS

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    1. Nadinath B. Nillegoda & Janine Kirstein & Anna Szlachcic & Mykhaylo Berynskyy & Antonia Stank & Florian Stengel & Kristin Arnsburg & Xuechao Gao & Annika Scior & Ruedi Aebersold & D. Lys Guilbride & R, 2015. "Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation," Nature, Nature, vol. 524(7564), pages 247-251, August.
    2. Eilika U. Weber-Ban & Brian G. Reid & Andrew D. Miranker & Arthur L. Horwich, 1999. "Global unfolding of a substrate protein by the Hsp100 chaperone ClpA," Nature, Nature, vol. 401(6748), pages 90-93, September.
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