Abstract:
:Apolipoprotein A-I (apoA-I) is the main protein of plasma high-density lipoproteins (HDL, or good cholesterol) that remove excess cell cholesterol and protect against atherosclerosis. In hereditary amyloidosis, mutations in apoA-I promote its proteolysis and the deposition of the 9-11 kDa N-terminal fragments as fibrils in vital organs such as kidney, liver, and heart, causing organ damage. All known amyloidogenic mutations in human apoA-I are clustered in two residue segments, 26-107 and 154-178. The X-ray crystal structure of the C-terminal truncated human protein, Δ(185-243)apoA-I, determined to 2.2 Å resolution by Mei and Atkinson, provides the structural basis for understanding apoA-I destabilization in amyloidosis. The sites of amyloidogenic mutations correspond to key positions within the largely helical four-segment bundle comprised of residues 1-120 and 144-184. Mutations in these positions disrupt the bundle structure and destabilize lipid-free apoA-I, thereby promoting its proteolysis. Moreover, many mutations place a hydrophilic or Pro group in the middle of the hydrophobic lipid-binding face of the amphipathic α-helices, which will likely shift the population distribution from HDL-bound to lipid-poor/free apoA-I that is relatively unstable and labile to proteolysis. Notably, the crystal structure shows segment L44-S55 in an extended conformation consistent with the β-strand-like geometry. Exposure of this segment upon destabilization of the four-segment bundle probably initiates the α-helix to β-sheet conversion in amyloidosis. In summary, we propose that the amyloidogenic mutations promote apoA-I proteolysis by destabilizing the protein structure not only in the lipid-free but also in the HDL-bound form, with segment L44-S55 providing a likely template for the cross-β-sheet conformation.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Gursky O,Mei X,Atkinson Ddoi
10.1021/bi2017014subject
Has Abstractpub_date
2012-01-10 00:00:00pages
10-8issue
1eissn
0006-2960issn
1520-4995journal_volume
51pub_type
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