Membrane properties and amyloid fibril formation of lung surfactant protein C.

Abstract

Pulmonary surfactant is essential for respiration and lung host defence and is composed of 80-90% lipids, mainly dipalmitoylphosphatidylcholine (DPPC). Surfactant protein C (SP-C) constitutes 1-2% of the surfactant mass, and is one of the most hydrophobic peptides yet isolated. SP-C residues 9-34 form an alpha-helix with a central poly-valine segment, which perfectly matches the thickness of a fluid DPPC bilayer. The palmitoyl groups linked to Cys-5 and Cys-6 of SP-C increase the capacity of the peptide to promote lipid adsorption at an air/liquid interface, and augment the mechanical stability of SP-C/lipid mixtures. SP-C undergoes alpha-helix-->beta-sheet transition and forms amyloid fibrils. NMR and MS studies show that the poly-valine helix is kinetically stabilized, and that once it unfolds, formation of beta-sheet aggregates is significantly faster than refolding. alpha-Helix unfolding is accelerated after removal of the palmitoyl groups. Secondary structure prediction of SP-C yields beta-strand conformation of the poly-valine part. A database search revealed similar discordance between experimentally determined helices and predicted beta-strands for other amyloid-forming proteins, including the prion protein associated with spongiform encephalopathies, and the amyloid-beta (Abeta) peptide associated with Alzheimer's disease. For Abeta and SP-C, removal of the helix/strand discordance by residue replacements abrogates fibril formation in vitro.