High-resolution structure of a BRICHOS domain and its implications for anti-amyloid chaperone activity on lung surfactant protein C
2012
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 exchangemass 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 diseasesecondary to intramolecular chaperone malfunction.
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