The Crystal Structure of the C-Terminal Truncated Apolipoprotein A-I Sheds New Light on Amyloid Formation by the N-Terminal Fragment
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- 作者：Olga Gursky ; Xiaohu Mei ; David Atkinson
- 刊名：Biochemistry
- 出版年：2012
- 出版时间：January 10, 2012
- 年：2012
- 卷：51
- 期：1
- 页码：10-18
- 全文大小：367K
- 年卷期：v.51,no.1(January 10, 2012)
- ISSN：1520-4995
文摘
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鈥?1 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鈥?07 and 154鈥?78. The X-ray crystal structure of the C-terminal truncated human protein, 螖(185鈥?43)apoA-I, determined to 2.2 脜 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鈥?20 and 144鈥?84. 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 伪-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鈥揝55 in an extended conformation consistent with the 尾-strand-like geometry. Exposure of this segment upon destabilization of the four-segment bundle probably initiates the 伪-helix to 尾-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鈥揝55 providing a likely template for the cross-尾-sheet conformation.