Dual role of an N-terminal amyloidogenic mutation in apolipoprotein A-I: destabilization of helix bundle and enhancement of fibril formation.

ABSTRACT: A number of naturally occurring mutations of apolipoprotein (apo) A-I, the major protein of HDL, are known to be associated with hereditary amyloidosis and atherosclerosis. Here, we examined the effects of the G26R point mutation in apoA-I (apoA-I(Iowa)) on the structure, stability, and aggregation propensity to form amyloid fibril of full-length apoA-I and the N-terminal fragment of apoA-I. Circular dichroism and fluorescence measurements demonstrated that the G26R mutation destabilizes the N-terminal helix bundle domain of full-length protein, leading to increased hydrophobic surface exposure, whereas it has no effect on the initial structure of the N-terminal 1-83 fragment, which is predominantly a random coil structure. Upon incubation for extended periods at neutral pH, the N-terminal

SUBMITTER: Adachi E 

PROVIDER: S-EPMC3554949 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature