Willander, Hanna
- Institutionen för husdjurens biovetenskaper, Sveriges lantbruksuniversitet
Forskningsartikel2012Vetenskapligt granskadÖppen tillgång
Willander, Hanna; Askarieh, Glareh; Nordling, Kerstin; Hermansson, Erik; Presto, Jenny; Knight, Stefan David; Johansson, Jan
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.
interstitial lung disease; SFTPC mutations; beta-sheet aggregates; transmembrane segment; discordant helix
Proceedings of the National Academy of Sciences
2012, volym: 109, nummer: 7, sidor: 2325-2329
Utgivare: NATL ACAD SCIENCES
SDG3 God hälsa och välbefinnande
Cell- och molekylärbiologi
https://res.slu.se/id/publ/68317