Abstract
The physiological link between circulating high density lipoprotein (HDL) levels and cardiovascular disease is well-documented, albeit its intricacies are not well-understood. An improved appreciation of HDL function and overall role in vascular health and disease requires at its foundation a better understanding of the lipoprotein's molecular structure, its formation, and its process of maturation through interactions with various plasma enzymes and cell receptors that intervene along the pathway of reverse cholesterol transport. This review focuses on summarizing recent developments in the field of lipid free apoA-I and HDL structure, with emphasis on new insights revealed by newly published nascent and spherical HDL models constructed by combining low resolution structures obtained from small angle neutron scattering (SANS) with contrast variation and geometrical constraints derived from hydrogen–deuterium exchange (HDX), crosslinking mass spectrometry, electron microscopy, Förster resonance energy transfer, and electron spin resonance. Recently published low resolution structures of nascent and spherical HDL obtained from SANS with contrast variation and isotopic labeling of apolipoprotein A-I (apoA-I) will be critically reviewed and discussed in terms of how they accommodate existing biophysical structural data from alternative approaches. The new low resolution structures revealed and also provided some answers to long standing questions concerning lipid organization and particle maturation of lipoproteins. The review will discuss the merits of newly proposed SANS based all atom models for nascent and spherical HDL, and compare them with accepted models. Finally, naturally occurring and bioengineered mutations in apoA-I, and their impact on HDL phenotype, are reviewed and discuss together with new therapeutics employed for restoring HDL function.
Highlights
Decades of research have confirmed that high density lipoprotein (HDL), a plasma cholesterol carrier, is anti-atherogenic and antiinflammatory in its native state, it gains atherogenic and pro-inflammatory properties when it becomes dysfunctional via systemic and vascular inflammation (Rosenson et al, 2016)
While several studies initiated the debate on how strongly plasma HDL levels correlate with cardiovascular disease (CAD; Vergeer et al, 2010), recent advances in understanding the structure of HDL and its multiple physiological functions suggest that chemical modifications of its main protein component, apolipoprotein A-I by oxidative/nitrating agents generated by myeloperoxidase (MPO), are to a great extend responsible for loss of function and the accumulation of dysfunctional heavily oxidized and crosslinked apoA-I in the artery wall (Smith, 2010; DiDonato et al, 2013, 2014; Huang et al, 2013, 2014; Rosenson et al, 2016)
This review is not intended to be a comprehensive presentation of published experimental and theoretical studies about the structure and function of HDL. For such information the reader is directed to reviews by Brouillette and Anantharamaiah (1995), Thomas et al (2008), Phillips et al (Lund-Katz and Phillips, 2010; Phillips, 2013), and Rosenson et al (2016) Rather, this paper focuses on reviewing recently published experimental data and theoretical models of lipid free apoA-I and low resolution structures of nascent HDL (nHDL) and spherical HDL obtained from small angle neutron scattering (SANS) with contrast variation and isotopic labeling of apoA-I
Summary
Decades of research have confirmed that high density lipoprotein (HDL), a plasma cholesterol carrier, is anti-atherogenic and antiinflammatory in its native state, it gains atherogenic and pro-inflammatory properties when it becomes dysfunctional via systemic and vascular inflammation (Rosenson et al, 2016). The lack of a high resolution crystal structure for the full length protein and the need to understand apoA-I physiological properties like cholesterol efflux, HDL maturation, lipid exchange with cell receptors, etc., stimulated the development of all atom theoretical models for lipid free apoA-I in solution (Figure 2), constructed by incorporating many of the biophysical data gathered from monoclonal antibody, calorimetry (DSC), and limited proteolysis studies, and various geometrical constraints derived from 13C NMR, MS-crosslinks, spin coupling (EPR), FRET, and HDX (Jonas et al, 1990; Collet et al, 1991; Marcel et al, 1991; Sparks et al, 1992a; Calabresi et al, 1993; Tricerri et al, 2001; Silva et al, 2005b; Chetty et al, 2009; Jones et al, 2010; Lagerstedt et al, 2012; Pollard et al, 2013). This hypothesis regarding the origin of crosslink K88–K118 reported for 1 mg/mL apoA-I by Pollard et al (2013) is supported by the observation made by Silva et al (2005b) that lipid free apoA-I contains multimers at concentrations as low as 0.1 mg/mL apoA-I
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