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

Kristine F. R. Pobre-Piza, Melissa J. Mann, Ashley R. Flory and Linda M. Hendershot ()
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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

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29478-z

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