Identification of an Apolipoprotein A-I Structural Element That Mediates Cellular Cholesterol Efflux and Stabilizes ATP Binding Cassette Transporter A1
Synthetic peptides were used in this study to identify a structural element of apolipoprotein (apo) A-I that stimulates cellular cholesterol efflux and stabilizes the ATP binding cassette transporter A1 (ABCA1). Peptides (22-mers) based on helices 1 (amino acids 44â65) and 10 (amino acids 220â24...
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Veröffentlicht in: | The Journal of biological chemistry 2004-06, Vol.279 (23), p.24044-24052 |
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Sprache: | eng |
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Zusammenfassung: | Synthetic peptides were used in this study to identify a structural element of apolipoprotein (apo) A-I that stimulates cellular
cholesterol efflux and stabilizes the ATP binding cassette transporter A1 (ABCA1). Peptides (22-mers) based on helices 1 (amino
acids 44â65) and 10 (amino acids 220â241) of apoA-I had high lipid binding affinity but failed to mediate ABCA1-dependent
cholesterol efflux, and they lacked the ability to stabilize ABCA1. The addition of helix 9 (amino acids 209â219) to either
helix 1 (creates a 1/9 chimera) or 10 (9/10 peptide) endowed cholesterol efflux capability and ABCA1 stabilization activity
similar to full-length apoA-I. Adding helix 9 to helix 1 or 10 had only a small effect on lipid binding affinity compared
with the 22-mer peptides, indicating that helix length and/or determinants on the polar surface of the amphipathic α-helices
is important for cholesterol efflux. Cholesterol efflux was specific for the structure created by the 1/9 and 9/10 helical
combinations, as 33-mers composed of helices 1 and 3 (1/3), 2/9, and 4/9 failed to mediate cholesterol efflux in an ABCA1-dependent
manner. Transposing helices 9 and 10 (10/9 peptide) did not change the class Y structure, hydrophobicity, or amphiphilicity
of the helical combination, but the topography of negatively charged amino acids on the polar surface was altered, and the
10/9 peptide neither mediated ABCA1-dependent cholesterol efflux nor stabilized ABCA1 protein. These results suggest that
a specific structural element possessing a linear array of acidic residues spanning two apoA-I amphipathic α-helices is required
to mediate cholesterol efflux and stabilize ABCA1. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M400561200 |