Abstract
A number of amyloidogenic variants of apoA-I have been discovered but most have not
been analyzed. Previously, we showed that the G26R mutation of apoA-I leads to
increased β-strand structure, increased N-terminal protease susceptibility, and
increased fibril formation after several days of incubation. In vivo, this and other
variants mutated in the N-terminal domain (residues 26 to ∼90) lead to renal and
hepatic accumulation. In contrast, several mutations identified within residues 170
to 178 lead to cardiac, laryngeal, and cutaneous protein deposition. Here, we
describe the structural changes in the fibrillogenic variant L178H. Like G26R, the
initial structure of the protein exhibits altered tertiary conformation relative to
wild-type protein along with decreased stability and an altered lipid binding
profile. However, in contrast to G26R, L178H undergoes an increase in helical
structure upon incubation at 37°C with a half time (t
1/2
) of about 12
days. Upon prolonged incubation, the L178H mutant forms fibrils of a diameter of 10
nm that ranges in length from 30 to 120 nm. These results show that apoA-I, known for
its dynamic properties, has the ability to form multiple fibrillar conformations,
which may play a role in the tissue-specific deposition of the individual
variants.