High-resolution structure of a BRICHOS domain and its implications for anti-amyloid chaperone activity on lung surfactant protein C
2012 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 7, 2325-2329 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2012. Vol. 109, no 7, 2325-2329 p.
interstitial lung disease, SFTPC mutations, beta-sheet aggregates, transmembrane segment, discordant helix
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-171673DOI: 10.1073/pnas.1114740109ISI: 000300489200038OAI: oai:DiVA.org:uu-171673DiVA: diva2:512249