Amyloidogenic mutations in human apolipoprotein A-I are not necessarily destabilizing - a common mechanism of apolipoprotein A-I misfolding in familial amyloidosis and atherosclerosis.

ABSTRACT: High-density lipoproteins and their major protein, apolipoprotein A-I (apoA-I), remove excess cellular cholesterol and protect against atherosclerosis. However, in acquired amyloidosis, nonvariant full-length apoA-I deposits as fibrils in atherosclerotic plaques; in familial amyloidosis, N-terminal fragments of variant apoA-I deposit in vital organs, damaging them. Recently, we used the crystal structure of Δ(185-243)apoA-I to show that amyloidogenic mutations destabilize apoA-I and increase solvent exposure of the extended strand 44-55 that initiates β-aggregation. In the present study, we test this hypothesis by exploring naturally occurring human amyloidogenic mutations, W50R and G26R, within or close to this strand. The mutations caused small changes in the protein's α-helical content,

SUBMITTER: Das M 

PROVIDER: S-EPMC4047191 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature