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

H Willander, G Askarieh, M Landreh… - Proceedings of the …, 2012 - National Acad Sciences
H Willander, G Askarieh, M Landreh, P Westermark, K Nordling, H Keränen, E Hermansson…
Proceedings of the National Academy of Sciences, 2012National Acad Sciences
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 …
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.
National Acad Sciences