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

Sammanfattning

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.

Nyckelord

interstitial lung disease; SFTPC mutations; beta-sheet aggregates; transmembrane segment; discordant helix

Publicerad i

Proceedings of the National Academy of Sciences
2012, volym: 109, nummer: 7, sidor: 2325-2329
Utgivare: NATL ACAD SCIENCES

SLU författare

• Willander, Hanna

  • Institutionen för husdjurens biovetenskaper, Sveriges lantbruksuniversitet
    

• Askarieh, Glareh

  • Institutionen för molekylärbiologi, Sveriges lantbruksuniversitet
    

• Nordling, Kerstin

  • Institutionen för husdjurens biovetenskaper, Sveriges lantbruksuniversitet
    

• Hermansson, Erik

  • Institutionen för husdjurens biovetenskaper, Sveriges lantbruksuniversitet
    

• Presto, Jenny

  • Institutionen för husdjurens biovetenskaper, Sveriges lantbruksuniversitet
    

• Knight, Stefan David

  • Institutionen för molekylärbiologi, Sveriges lantbruksuniversitet
    

• Johansson, Jan

  • Institutionen för husdjurens biovetenskaper, Sveriges lantbruksuniversitet
    

Globala målen (SDG)

SDG3 God hälsa och välbefinnande

UKÄ forskningsämne

Cell- och molekylärbiologi

Publikationens identifierare

• DOI: https://doi.org/10.1073/pnas.1114740109

Permanent länk till denna sida (URI)

https://res.slu.se/id/publ/68317