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
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.