Amyloid fibril formation by pulmonary surfactant protein C

Abstract

Lung surfactant protein C (SP-C) is a lipopeptide that contains two fatty acyl (palmitoyl) chains bound via intrinsically labile thioester bonds. SP-C can transform from a monomeric K K-helix into L L-sheet aggregates, reminiscent of structural changes that are supposed to occur in amyloid fibril formation. SP-C is here shown to form amyloid upon incubation in solution. Furthermore, one patient with pulmonary alveolar proteinosis (PAP, a rare disease where lung surfactant proteins and lipids accumulate in the airspaces) and six healthy controls have been studied regarding presence and composition of amyloid fibrils in the cell-free fraction of bronchoalveolar lavage (BAL) fluid. Abundant amyloid fibrils were found in BAL fluid from the patient with PAP and, in low amounts, in three of the six healthy controls. SDS-insoluble fibrillar material associated with PAP mainly consists of SP-C, in contrast to the fibrils found in controls. Fibrillated SP-C has to a significant extent lost the palmitoyl groups, and removal of the palmitoyl groups in vitro increases the rate of fibril formation.z 1999 Federation of European Biochemical Societies.

Biosynthesis of Surfactant Protein C (SP-C)

“…The ␣-helical form of SP-C seems to be thermodynamically most stable in a micellar environment, whereas upon removal from lipid, it transforms into insoluble ␤-sheet aggregates as a result of a high kinetic barrier for unfolding in aqueous solvents (5). In fact, if left in aqueous solutions, it can go on to form insoluble amyloid fibrils (6,41). Therefore, any conditions that compromise the integrity of the ␣-helical structure of the transmembrane domain (e.g.…”

Specific Chaperones and Regulatory Domains in Control of Amyloid Formation

“…As a consequence, the SP-C helix is unable to refold into the helical structure once it has unfolded, and then instead aggregates (23). The insoluble, aggregated form of SP-C contains a ␤-sheet structure and shows abundant amyloid-like fibrils (24). In sharp contrast to the native poly-Val structure, a poly-Leu analogue of SP-C has a high helix propensity (19) and results in a dramatic increase in the spontaneous formation of a stable ␣-helix with no signs of amyloid fibril formation (25).…”

Mutations linked to interstitial lung disease can abrogate anti-amyloid function of prosurfactant protein C

“…In order to study SP-C in its natural phospholipid environment, a lung surfactant preparation containing phospholipids, SP-C and SP-B, was incubated at room temperature for 7 and 14 days and thereafter subjected to an SDS extraction procedure previously used for isolation of fibrillar amyloid β-peptide from brain tissue of Alzheimer's disease patients [32], or SP-C fibrils from PAP patients [9]. At time 0 no aggregates were observed, but after 7 or 14 days SP-C had aggregated into amyloid-like fibrils, as seen by electron microscopy ( Fig.…”