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Publication
Apolipoprotein A-I modulates HDL particle size in the absence of apolipoprotein
A-II.
Authors Melchior JT, Street SE, Vaisar T, Hart R, Jerome J, Kuklenyik Z, Clouet-Foraison
N, Thornock C, Bedi S, Shah AS, Segrest JP, Heinecke JW, Davidson WS
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal Journal of lipid research
Year 2021
Date Published 7/1/2021
Volume : Pages 62 : 100099
PubMed Reference 34324889
Abstract Human high-density lipoproteins (HDLs) are a complex mixture of structurally
related nanoparticles that perform distinct physiological functions. We
previously showed that human HDL containing apolipoprotein A-I (APOA1) but not
apolipoprotein A-II (APOA2), designated LpA-I, is composed primarily of two
discretely sized populations. Here, we isolated these particles directly from
human plasma by antibody affinity chromatography, separated them by
high-resolution size-exclusion chromatography and performed a deep molecular
characterization of each species. The large and small LpA-I populations were
spherical with mean diameters of 109 Å and 91 Å, respectively. Unexpectedly,
isotope dilution MS/MS with [15N]-APOA1 in concert with quantitation of particle
concentration by calibrated ion mobility analysis demonstrated that the large
particles contained fewer APOA1 molecules than the small particles; the
stoichiometries were 3.0 and 3.7 molecules of APOA1 per particle, respectively.
MS/MS experiments showed that the protein cargo of large LpA-I particles was
more diverse. Human HDL and isolated particles containing both APOA1 and APOA2
exhibit a much wider range and variation of particle sizes than LpA-I,
indicating that APOA2 is likely the major contributor to HDL size heterogeneity.
We propose a ratchet model based on the trefoil structure of APOA1 whereby the
helical cage maintaining particle structure has two "settings"-large and
small-that accounts for these findings. This understanding of the determinants
of HDL particle size and protein cargo distribution serves as a basis for
determining the roles of HDL subpopulations in metabolism and disease states.




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