Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 7, Pages 2325-2329Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1114740109
Keywords
interstitial lung disease; SFTPC mutations; beta-sheet aggregates; transmembrane segment; discordant helix
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Funding
- Swedish Research Council
- Spanish Ministry for Research and Innovation
- NIH [HL-082747, HL-65174]
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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.
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