Willander, Hanna
- Department of Animal Biosciences, Swedish University of Agricultural Sciences
Research article2012Peer reviewedOpen access
High-resolution structure of a BRICHOS domain and its implications for anti-amyloid chaperone activity on lung surfactant protein C
Willander, Hanna; Askarieh, Glareh; Nordling, Kerstin; Hermansson, Erik; Presto, Jenny; Knight, Stefan David; Johansson, Jan
Abstract
BRICHOS domains are encoded in >30 human genes, which are associated with cancer, neurodegeneration, and interstitial lung disease (ILD). The BRICHOS domain from lung surfactant protein C proprotein (proSP-C) is required for membrane insertion of SP-C and has anti-amyloid activity in vitro. Here, we report the 2.1 angstrom crystal structure of the human proSP-C BRICHOS domain, which, together with molecular dynamics simulations and hydrogen-deuterium exchange mass spectrometry, reveals how BRICHOS domains may mediate chaperone activity. Observation of amyloid deposits composed of mature SP-C in lung tissue samples from ILD patients with mutations in the BRICHOS domain or in its peptide-binding linker region supports the in vivo relevance of the proposed mechanism. The results indicate that ILD mutations interfering with proSP-C BRICHOS activity cause amyloid disease secondary to intramolecular chaperone malfunction.
Keywords
interstitial lung disease; SFTPC mutations; beta-sheet aggregates; transmembrane segment; discordant helix
Published in
Proceedings of the National Academy of Sciences
2012, Volume: 109, number: 7, pages: 2325-2329
Publisher: NATL ACAD SCIENCES
Askarieh, Glareh
- Department of Molecular Biology, Swedish University of Agricultural Sciences
- Department of Molecular Biology, Swedish University of Agricultural Sciences
Nordling, Kerstin
- Department of Animal Biosciences, Swedish University of Agricultural Sciences
- Department of Animal Biosciences, Swedish University of Agricultural Sciences
Hermansson, Erik
- Department of Animal Biosciences, Swedish University of Agricultural Sciences
- Department of Animal Biosciences, Swedish University of Agricultural Sciences
Presto, Jenny
- Department of Animal Biosciences, Swedish University of Agricultural Sciences
- Department of Animal Biosciences, Swedish University of Agricultural Sciences
Knight, Stefan David
- Department of Molecular Biology, Swedish University of Agricultural Sciences
- Department of Molecular Biology, Swedish University of Agricultural Sciences
Johansson, Jan
- Department of Animal Biosciences, Swedish University of Agricultural Sciences
- Department of Animal Biosciences, Swedish University of Agricultural Sciences
SLU Authors
Sustainable Development Goals
Ensure healthy lives and promote well-being for all at all ages
UKÄ Subject classification
Cell and Molecular Biology
Publication identifier
DOI: https://doi.org/10.1073/pnas.1114740109
Permanent link to this page (URI)
https://res.slu.se/id/publ/68317