Anti-amyloid activity of the C-terminal domain of proSP-C against amyloid beta-peptide and medin.
Amyloid fibrils are found in approximately 25 different diseases, including Alzheimer's disease. Lung surfactant protein C (SP-C) forms fibrils in association with pulmonary disease. It was recently found that the C-terminal domain of proSP-C (CTC), which is localized to the endoplasmic reticulum (ER) lumen, protects the transmembrane (TM) part of (pro)SP-C from aggregation into amyloid until it has a folded into an alpha-helix. CTC appears to have a more general anti-amyloid effect by also acting on TM regions of other proteins. Here we investigate interactions of CTC with the amyloid beta-peptide (Abeta) associated with Alzheimer's disease and medin, a peptide that forms fibrils in the most common form of human amyloid. CTC prevents fibril formation in Abeta and medin and forms a complex with Abeta oligomers, as judged by size-exclusion chromatography and electrospray ionization mass spectrometry. These data suggest that CTC functions as a chaperone that acts preferentially against unfolded TM segments and structural motifs found during amyloid fibril formation, a mechanism that may be exploited in forming a basis for future anti-amyloid therapy.
Nerelius
Charlotte
C
Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, The Biomedical Centre, 751 23 Uppsala, Sweden.
Gustafsson
Magnus
M
Nordling
Kerstin
K
Larsson
Annika
A
Johansson
Jan
J
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000648:ultrastructure; D000954:Antigens, Surface / Q000648:ultrastructure; D006801:Humans; D008894:Milk Proteins / Q000037:antagonists & inhibitors* / Q000648:ultrastructure; D018832:Molecular Chaperones / Q000737:chemistry / Q000502:physiology / Q000648:ultrastructure; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000648:ultrastructure; D017510:Protein Folding; D011498:Protein Precursors / Q000502:physiology* / Q000648:ultrastructure; D017434:Protein Structure, Tertiary / Q000502:physiology; D037721:Pulmonary Surfactant-Associated Protein C / Q000737:chemistry / Q000502:physiology* / Q000648:ultrastructure
D016229:Amyloid beta-Peptides; D000954:Antigens, Surface; C098942:MFGE8 protein, human; D008894:Milk Proteins; D018832:Molecular Chaperones; D010446:Peptide Fragments; D011498:Protein Precursors; D037721:Pulmonary Surfactant-Associated Protein C; C078592:amyloid beta-protein (1-40)