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Amyloid Formation by Human Apolipoproteins: Sequence Analyses and Structural Insights
Author(s) -
Gursky Olga,
Das Madhurima
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.564.5
Subject(s) - apolipoprotein b , biochemistry , chemistry , amyloid (mycology) , protein folding , apolipoprotein e , amyloid fibril , serum amyloid a , amphiphile , biology , amyloid β , cholesterol , disease , medicine , immunology , inorganic chemistry , organic chemistry , copolymer , inflammation , polymer
Apolipoproteins are protein components of lipoproteins that transport lipids in circulation and are central to cardiovascular health and disease. Apolipoprotein dissociation from the lipid renders them labile to misfolding that is implicated in atherosclerosis, systemic amyloidoses and Alzheimer's disease. We used 12 bioinformatics approaches to assess amyloid‐forming potential of 10 members of this protein family and identify segments that initiate aggregation. Mapping such segments on the available atomic structures helps explain why some apolipoproteins readily form amyloid while others do not. We show that nearly all amyloidogenic segments are hydrophobic, are located in the native lipid‐binding amphipathic a‐helices or b‐sheets, and are likely to form parallel in‐register beta‐sheet in amyloid. These predictions have been verified experimentally for several proteins. Surprisingly, the rank order of the sequence propensity to form amyloid (apoB > apoA‐II > apoC‐II 蠅 apoA‐I, apoC‐III, SAA, apoC‐I> apoA‐IV, apoA‐V, apoE) does not correlate with the proteins' involvement in amyloidosis. Rather, it correlates directly with the strength of the protein‐lipid association, which increases with increasing protein hydrophobicity. Therefore, the lipid surface‐binding function and the amyloid‐forming propensity are both rooted in apolipoproteins' hydrophobicity, suggesting that functional constraints make it difficult to completely eliminate pathogenic apolipoprotein misfolding. We propose that apolipoproteins have evolved protective mechanisms against misfolding, such as the sequestration of the amyloidogenic segments via the native protein‐lipid and protein‐protein interactions involving amphipathic a‐helices or b‐sheets. Funded by NIH GM067260.