High-resolution structure of a BRICHOS domain and its implications for anti-amyloid chaperone activity on lung surfactant protein C

Hanna Willander, Glareh Askarieh, Michael Landreh, Per Westermark, Kerstin Nordling, Henrik Keränen, Erik Hermansson, Aaron Hamvas, Lawrence M. Noge, Tomas Bergman, Alejandra Saenz, Cristina Casals, Johan Åqvist, Hans Jörnvall, Helena Berglund, Jenny Presto, Stefan D. Knight, Jan Johansson

Research output: Contribution to journalArticle

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 Åcrystal 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.

Original languageEnglish (US)
Pages (from-to)2325-2329
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number7
DOIs
StatePublished - Feb 14 2012

Keywords

  • Discordant helix
  • Interstitial lung disease
  • SFTPC mutations
  • Transmembrane segment
  • β-sheet aggregates

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'High-resolution structure of a BRICHOS domain and its implications for anti-amyloid chaperone activity on lung surfactant protein C'. Together they form a unique fingerprint.

  • Cite this

    Willander, H., Askarieh, G., Landreh, M., Westermark, P., Nordling, K., Keränen, H., Hermansson, E., Hamvas, A., Noge, L. M., Bergman, T., Saenz, A., Casals, C., Åqvist, J., Jörnvall, H., Berglund, H., Presto, J., Knight, S. D., & Johansson, J. (2012). High-resolution structure of a BRICHOS domain and its implications for anti-amyloid chaperone activity on lung surfactant protein C. Proceedings of the National Academy of Sciences of the United States of America, 109(7), 2325-2329. https://doi.org/10.1073/pnas.1114740109