Correlation of Structural Stability with Functional Remodeling of High-Density Lipoproteins: The Importance of Being Disordered

Abstract

High-density lipoproteins (HDLs) are protein-lipid assemblies that remove excess cell cholesterol and prevent atherosclerosis. HDL are stabilized by kinetic barriers that decelerate protein dissociation and lipoprotein fusion. We propose that similar barriers modulate metabolic remodeling of plasma HDLs; hence, changes in particle composition that destabilize HDLs and accelerate their denaturation may accelerate their metabolic remodeling. To test this notion, we correlate existing reports on HDLmediated cell cholesterol efflux and esterification, which are obligatory early steps in cholesterol removal, with our kinetic studies of HDL stability. The results support our hypothesis and show that factors accelerating cholesterol efflux and esterification in model discoidal lipoproteins (including reduced protein size, reduced fatty acyl chain length and/or increased cis-unsaturation) destabilize lipoproteins and accelerate their fusion and apolipoprotein dissociation. Oxidation studies of plasma spherical HDL show a similar trend: mild oxidation by Cu 2+ or OCl -accelerates cell cholesterol efflux, protein dissociation and HDL fusion, while extensive oxidation inhibits these reactions. Consequently, moderate destabilization may benefit HDL functions by facilitating insertion of cholesterol and lipophilic enzymes, promoting dissociation of lipid-poor apolipoproteins, which are primary acceptors of cell cholesterol, and thereby accelerating HDL metabolism. Therefore, HDL stability must be delicately balanced to maintain structural integrity of the lipoprotein assembly and ensure structural specificity necessary for HDL interactions with its metabolic partners, while facilitating rapid HDL remodeling and turnover at key junctures of cholesterol transport. The inverse correlation between HDL stability and remodeling illustrates the functional importance of structural disorder in macromolecular assemblies stabilized by kinetic barriers. KeywordsKinetic stability; apolipoprotein dissociation; lipoprotein fusion; reverse cholesterol transport; structural disorder; atherosclerosis High-density lipoproteins (HDLs) are heterogeneous complexes 7-13 nm in diameter that are composed of several major proteins (termed apolipoproteins), many minor proteins, and variable amounts of lipid molecules. Plasma concentrations of HDL and its major protein, apoA-I (243 a.a.), correlate inversely with the risk of developing coronary artery disease (reviewed in (1,2)). This cardioprotection results from the central role of HDLs in reverse cholesterol transport (RCT) and from their anti-oxidant and anti-inflammatory action (3). RCT is the sole pathway of cholesterol removal from peripheral tissues to the liver for excretion or to steroidogenic organs for hormone synthesis (1). During RCT, cell cholesterol is taken up by nascent discoidal HDLs or their lipid-poor precursors (4), esterified by lecithin:cholesterol acyltransferase (LCAT), and sequestered in the core of HDLs, thereby converting them to mature spherical particles (Fig. 1, ...

Effects of cholesterol on thermal stability of discoidal high density lipoproteins

“…In fact, transient openings in HDL surface may facilitate insertion of cholesterol, LCAT, and other plasma factors, which is necessary for HDL remodeling in RCT ( 37,38 ). This notion is consistent with an inverse relation observed between the stability of HDL subclasses and their functions in RCT (37)(38)(39).…”

Unraveling the complexities of the HDL lipidome

“…The requirement of the fl uid lipid phase for cholesterol effl ux can be viewed in the context of the concept of HDL structural lability as a prerequisite for this process ( 54 ). According to this view, compositional changes that destabilize HDL particles may accelerate their metabolic remodeling, including that which occurs during cellular lipid effl ux.…”

“…According to this view, compositional changes that destabilize HDL particles may accelerate their metabolic remodeling, including that which occurs during cellular lipid effl ux. Such compositional changes may include reduced chain length and an increased level of unsaturation of fatty acid residues in surface phospholipids ( 54,55 ).…”

New insights into the determination of HDL structure by apolipoproteins

“…The process is enthalpically driven, with the enthalpy of binding being linearly correlated with the number of amino acids forming ␣ -helix upon lipid binding ( 57 ). The increase in different conformations; this low stability structure facilitates functional remodeling of HDL particles ( 47 ). The helix bundle structure can be very sensitive to perturbation by point mutations.…”