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Conformational flexibility of apolipoprotein A-I amino- and carboxy-termini is
necessary for lipid binding but not cholesterol efflux.
Bedi S, Morris J, Shah A, Hart RC, Jerome WG, Aller SG, Tang C, Vaisar T,
Bornfeldt KE, Segrest JP, Heinecke JW, Davidson WS
Submitted Externally on 6/21/2022
Journal of lipid research
Volume : Pages
63 : 100168
Because of its critical role in HDL formation, significant efforts have been
devoted to studying apolipoprotein A-I (APOA1) structural transitions in
response to lipid binding. To assess the requirements for the conformational
freedom of its termini during HDL particle formation, we generated three dimeric
APOA1 molecules with their termini covalently joined in different combinations.
The dimeric (d)-APOA1C-N mutant coupled the C-terminus of one APOA1 molecule to
the N-terminus of a second with a short alanine linker, whereas the d-APOA1C-C
and d-APOA1N-N mutants coupled the C-termini and the N-termini of two APOA1
molecules, respectively, using introduced cysteine residues to form disulfide
linkages. We then tested the ability of these constructs to generate
reconstituted HDL by detergent-assisted and spontaneous phospholipid
microsolubilization methods. Using cholate dialysis, we demonstrate WT and all
APOA1 mutants generated reconstituted HDL particles of similar sizes,
morphologies, compositions, and abilities to activate lecithin:cholesterol
acyltransferase. Unlike WT, however, the mutants were incapable of spontaneously
solubilizing short chain phospholipids into discoidal particles. We found
lipid-free d-APOA1C-N and d-APOA1N-N retained most of WT APOA1's ability to
promote cholesterol efflux via the ATP binding cassette transporter A1, whereas
d-APOA1C-C exhibited impaired cholesterol efflux. Our data support the double
belt model for a lipid-bound APOA1 structure in nascent HDL particles and refute
other postulated arrangements like the "double super helix." Furthermore, we
conclude the conformational freedom of both the N- and C-termini of APOA1 is
important in spontaneous microsolubilization of bulk phospholipid but is not
critical for ABCA1-mediated cholesterol efflux.
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Financial support for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (National MMPC, RRID:SCR_008997,
) under the MICROMouse Program, grants DK076169.
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