α-Syn lipoprotein nano particles.
α-Syn interacts with negatively charged lipids to form bilayer-like
particles with diameters ranging from ~19 to 28 nm (Fig.
25)[68]. When viewed from the top, the largest of these particles
has an ~6 nm thick ring that probably corresponds to the
region occupied by α-Syn. This ring is surrounded by a darker ring, the
gray inner ring in turn surrounds a darker circular core that probably
corresponds to a lipid bilayer. Experimental findings suggest that the
ratio of lipids to protein in some particles is relatively high and that
the particles have 8 - 10 α-Syn monomers per particle. CD studies
indicates a high degree of α-helical structure. The authors propose that
these particles resemble apolipoprotein particles in which amphipathic
α-helices reside on the surfaces of the lipid particles.
Here we explore a more precisely defined series of models in which the
Nt domains form α-helices and the NAC domains form β-hairpins that
comprise a Type 2 β-barrel (Fig. 25, b-g). The core of the hydrophobic
NAC β-barrel is filled with a lipid bilayer. Sy1-3 segments form
amphipathic α-helices oriented approximately parallel to the axis of the
β-barrel and positioned about 4 nm from its wall. Lipids fit between
antiparallel pairs of Sy1-3 helices where their negatively charged
head-groups interact with positively charged lysine side-chains of the
helices. Sy4-5 α-helices are approximately perpendicular to the Sy1-3
helices and connect them to the Sy6 β-strand of NAC. Some lipids
oriented parallel to those of the central bilayer likely fit between
these radial Sy4-5 helices. The smallest of our models has eight α-Syn
monomers. Three larger particles increase in size by steps of eight
monomers, consistent with the hypothesis that they form by mergers of
smaller particles. The thickness of the putative lipoprotein ring
remains constant as the particles increase in size from 8 to 16 to 24 to
32mers. Thus, as the numbers of monomers increase, the increase in the
diameter of the assembly equals the increase in the diameter of the
β-barrel. If S/N = 1.0 for all β-barrels, an increase of 16 strands
(i.e., of 8 NAC β-hairpins) increases the diameter by
~3.0 nm; i.e . if the diameter of the 8mer is 19
nm, then the next three larger particles will have diameters of
~ 22, 25, and 28 nm. The model dimensions are consistent
with the diameters and shapes of the lipoprotein disc CryoEM images.