High-resolution structure of a BRICHOS domain and its implications for anti-amyloid chaperone activity on lung surfactant protein C.
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 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.
Department of Anatomy, Physiology, and Biochemistry, Swedish University of Agricultural Sciences, S-751 24 Uppsala, Sweden.
Hanna
H
Willander
Glareh
G
Askarieh
Michael
M
Landreh
Per
P
Westermark
Kerstin
K
Nordling
Henrik
H
Keränen
Erik
E
Hermansson
Aaron
A
Hamvas
Lawrence M
LM
Nogee
Tomas
T
Bergman
Alejandra
A
Saenz
Cristina
C
Casals
Johan
J
Åqvistg
Hans
H
Jörnvall
Helena
H
Berglund
Jenny
J
Presto
Stefan D
SD
Knight
Jan
J
Johansson
D000595:Amino Acid Sequence; D000682:Amyloid / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D008168:Lung / Q000378:metabolism*; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D011487:Protein Conformation; D037721:Pulmonary Surfactant-Associated Protein C / Q000737:chemistry / Q000378:metabolism*
D000682:Amyloid; D018832:Molecular Chaperones; D037721:Pulmonary Surfactant-Associated Protein C