BRICHOS - a Novel Anti-Amyloid Chaperone : studies on pro-surfactant protein C

• Lung surfactant protein C (SP-C) is a 35-residue, transmembrane (TM) peptide that is extremely hydrophobic and lacks known homologous proteins. Due to a high content in Val residues in the α-helical TM part, SP-C can spontaneously convert into β-sheet aggregates. We show here that SP-C forms amyloid in interstitial lung disease (ILD) caused by mutations in the C-terminal part of proSP-C (CTC). CTC has been predicted to contain a ∼100-residue BRICHOS domain, found in 12 protein families with a wide range of functions and disease associations, such as respiratory distress syndrome, dementia and cancer. We hypothesised that the BRICHOS domain can act as a chaperone, preventing proprotein from misfolding during biosynthesis. Recombinant CTC can bind to lipid associated non-helical SP-C and this interaction results in an increased α-helical content in the mature SP-C peptide. Wildtype CTC can also stabilize proSP-C(1-58), which lacks the BRICHOS domain, and a proSP-C mutant in HEK293 cells. CTC binds selectively peptides derived from the TM part of SP-C and to residues that promote membrane insertion. CTC can also bind to other hydrophobic peptides, in particular the amyloid β-peptide (Aβ) associated with Alzheimer disease. CTC and Bri2 BRICHOS can prevent fibril formation of Aβ40 and Aβ42 far below stoichiometric amounts, indicating that BRICHOS may be useful in future therapy. The crystal structure of the BRICHOS domain from CTC shows a novel fold with a central β-sheet flanked by α-helices on either side. Many of the hydrophobic residues in the β-sheet are conserved and many of the point mutations associated with ILD coincide with these residues, suggesting that they are involved in the function of the BRICHOS domain possibly by binding substrate peptides. Taken together, results in this thesis, suggest that BRICHOS is a novel anti-amyloid chaperone domain and mutations that lead to BRICHOS dysfunction cause ILD and amyloid disease.

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NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

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