Abstract
Apolipoprotein A-I (apoA-I) in high-density lipoprotein (HDL) provides cardiovascular protection. Synchrotron radiation circular dichroism (SRCD) spectroscopy was used to analyze the dynamic solution structure of the apoA-I protein in the apo- and HDL-states and the protein structure conversion in HDL formation. Wild-type apoA-I protein was compared to human variants that either are protective (R173C, Milano) or lead to increased risk for ischaemic heart disease (A164S). Comparable secondary structure distributions in the HDL particles, including significant levels of beta strand/turn, were observed. ApoA-I Milano in HDL displayed larger size heterogeneity, increased protein flexibility, and an altered lipid-binding profile, whereas the apoA-I A164S in HDL showed decrease thermal stability, potentially linking the intrinsic HDL propensities of the variants to disease risk.
Highlights
Apolipoprotein A-I is the main protein component of high-density lipoprotein (HDL) and carries cholesterol and other lipids in blood circulation
As already discussed in the Introduction section, Apolipoprotein A-I (apoA-I) has a central role in the many functions of HDL in lipid and glucose transport and metabolism
The apoA-I protein is an attractive model to study protein structure dynamics in the formation of lipid-protein complexes, which is facilitated by abundant protein access either from blood plasma or from heterologous production of apoA-I, as well as the relatively small size of the protein (243 amino acids in the mature apoA-I) and the large conformational switch that occurs in the lipid-binding process
Summary
Apolipoprotein A-I (apoA-I) is the main protein component of high-density lipoprotein (HDL) and carries cholesterol and other lipids in blood circulation. Other beneficial effects of the apoA-I protein, including its anti-thrombotic and anti-oxidant functions, and a positive influence of apoA-I/ HDL on glucose control, with potential implications in the prevention and treatment of diabetes, have been demonstrated[2,3,4,5,6]. These features of the apoA-I protein have spurred large interests in exploring the translational medicine potential in cardiovascular disease and diabetes[7,8]. SRCD was chosen over conventional CD spectroscopy as the intense energy in SRCD spectroscopy allows for superior signal-to-noise ratio with negligible influence of the phospholipids on the signal in real-time, and for the determination of the secondary structure elements in both the presence and in the absence of phospholipids in a time-dependent manner[25]
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