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

Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2325-9. doi: 10.1073/pnas.1114740109. Epub 2012 Feb 2.


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 Å 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyloid / antagonists & inhibitors*
  • Crystallography, X-Ray
  • Lung / metabolism*
  • Models, Molecular
  • Molecular Chaperones / chemistry
  • Molecular Chaperones / metabolism*
  • Molecular Sequence Data
  • Protein Conformation
  • Pulmonary Surfactant-Associated Protein C / chemistry
  • Pulmonary Surfactant-Associated Protein C / metabolism*


  • Amyloid
  • Molecular Chaperones
  • Pulmonary Surfactant-Associated Protein C

Associated data

  • PDB/2YAD