2yad

Publication Abstract from PubMed

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 A 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.

High-resolution structure of a BRICHOS domain and its implications for anti-amyloid chaperone activity on lung surfactant protein C.,Willander H, Askarieh G, Landreh M, Westermark P, Nordling K, Keranen H, Hermansson E, Hamvas A, Nogee LM, Bergman T, Saenz A, Casals C, Aqvist J, Jornvall H, Berglund H, Presto J, Knight SD, Johansson J Proc Natl Acad Sci U S A. 2012 Feb 2. PMID:22308375^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.