Structural and dynamic features of apolipoprotein A-I cysteine mutants, Milano and Paris, in synthetic HDL

Structural basis for distinct functions of the naturally occurring Cys mutants of human apolipoprotein A-I

“…Another working assumption is that, similar conformations differ from all previously proposed models of apoA-I M or apoA-I P ( 10,38,58,59 ) which were based, in part, on the low-resolution structure of the N-terminally truncated ⌬ (1-43)apoA-I ( 3 ) and, hence, lacked the correct conformation of the 1-43 segment . As evident from the crystal structure of ⌬ (185-234)apoA-I, this segment forms an integral part of the four-segment bundle in apoA-I monomer or dimer (53) (Fig.…”

“…Again, our models differ from those previously proposed ( 59 ), as we incorporate the N-terminal conformation of apoA-I suggested by the atomic structure of ⌬ (185-243) apoA-I that only recently became available. Because apoA-IIcontaining heterodimers are not readily available in amounts suffi cient for detailed structural studies ( 59 ), these tentative models await their experimental verifi cation.…”

2,4-Furfurylidene-D-sorbitol and its tetra-methyl ether: synthesis, conformational studies, and radical scavenging activity

“…32 Production stage for both molecular dynamics simulations was performed with a timestep of 0.5 ps, for a total simulated time of 3 ns. The trajectories produced were subsequently analyzed with an R-script, measuring the H-H distances with an interactive tool.…”

Molecules That Mimic Apolipoprotein A-I: Potential Agents for Treating Atherosclerosis

“…Intriguingly, the Paris and Milano mutations, which exhibit similar cardioprotective effects despite reduced HDL levels, are Arg → Cys substitutions located at the same position of a helical segment but differing in which helix is affected. The apoA-IM variant undergoes faster proteolysis compared to normal apoA-I, , which can explain the lower plasma HDL levels. On the other hand, the source of the cardioprotective properties of these variants is not well understood, although the introduction of cysteine imparts improved antioxidant properties and allows formation of disulfide homodimers or heterodimers with other apolipoproteins. − ApoA-IM has been the subject of numerous in vivo studies, including human clinical trials, as detailed below.…”