Amyloid fibrils derived from the apolipoprotein A1 Leu174Ser variant contain elements of ordered helical structure

Citation
P. Mangione et al., Amyloid fibrils derived from the apolipoprotein A1 Leu174Ser variant contain elements of ordered helical structure, PROTEIN SCI, 10(1), 2001, pp. 187-199
Citations number
37
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
PROTEIN SCIENCE
ISSN journal
0961-8368 → ACNP
Volume
10
Issue
1
Year of publication
2001
Pages
187 - 199
Database
ISI
SICI code
0961-8368(200101)10:1<187:AFDFTA>2.0.ZU;2-J
Abstract
We recently described a new apolipoprotein Al variant presenting a Leu174Se r replacement mutation that is associated with a familial form of systemic amyloidosis displaying predominant heart involvement. We have now identifie d a second unrelated patient with very similar clinical presentation and ca rrying the identical apolipoprotein Al mutation. In this new patient the ma in protein constituent of the amyloid fibrils is the polypeptide derived fr om the first 93 residues of the protein, the identical fragment to that fou nd in the patient previously described to carry this mutation. The X-ray fi ber diffraction pattern obtained from preparations of partially aligned fib rils displays the cross-p reflections characteristic of all amyloid fibrils . In addition to these cross-p reflections, other reflections suggest the p resence of well-defined coiled-coil helical structure arranged with a defin ed orientation within the fibrils. In both cases the fibrils contain a trac e amount of full-length apolipoprotein Al with an apparent prevalence of th e wild-type species over the variant protein. We have found a ratio of full -length wild-type to mutant protein in plasma HDL of three to one. The poly peptide 1-93 purified from natural fibrils can be solubilized in aqueous so lutions containing denaturants, and after removal of denaturants it acquire s a monomeric state that, based on CD and NMR studies, has a predominantly random coil structure. The addition of phospholipids to the monomeric form induces the formation of some helical structure, thought most likely to occ ur at the C-terminal end of the polypeptide.