Cross-linking and amyloid formation by N- and C-terminal cysteine derivatives of human apolipoprotein C-II
| Autor: | Geoffrey J. Howlett, Chi L.L. Pham, Danny M. Hatters, Lynne J. Lawrence |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Amyloid
Apolipoprotein C-II Kinetics Fibril Biochemistry Dithiothreitol chemistry.chemical_compound Humans Cysteine Disulfides Apolipoproteins C biology Fibrillogenesis Peptide Fragments Crystallography Microscopy Electron Cross-Linking Reagents chemistry Cystatin C Covalent bond biology.protein Mutagenesis Site-Directed lipids (amino acids peptides and proteins) Dimerization |
| Zdroj: | Biochemistry. 41(48) |
| ISSN: | 0006-2960 |
| Popis: | We have investigated the effect of disulfide cross-linking on amyloid formation by human apolipoprotein (apo) C-II. Three derivatives of apoC-II were generated by inserting a cysteine residue on either the N-terminus (C(N)-apoC-II), C-terminus (C(C)-apoC-II), or both termini (C(N)C(C)-apoC-II). Under reducing conditions, all derivatives formed amyloid with a fibrous ribbon morphology similar to that of wild-type apoC-II. Under oxidizing conditions, C(N)- and C(N)C(C)-apoC-II formed a highly tangled network of fibrils, suggesting that the addition of an N-terminal cysteine to apoC-II promotes interfibril disulfide cross-links. Fibrils formed by C(C)-apoC-II under oxidizing conditions were closely packed but less tangled than fibrils formed by the C(N) and C(N)C(C) derivatives. The frequency of closed ring structures was more than doubled for C(C)-apoC-II compared to wild-type apoC-II. The kinetics of fibril formation by all cysteine derivatives was markedly enhanced under oxidizing conditions, suggesting that disulfide cross-linking promotes amyloid formation. Substoichiometric levels of preformed C(N)- and C(C)-apoC-II dimers accelerate amyloid formation by wild-type apoC-II. These data suggest that the N- and C-termini of apoC-II are close together in the amyloid fibril such that covalent cross-linking of either the N or C end of apoC-II promotes nucleation and the "seeding" of fibril growth. |
| Databáze: | OpenAIRE |
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