New insight into apolipoprotein A-I structure in high-density lipoprotein

A recent study provides new information that will further understanding of HDL structure, metabolism and function. Results of this study were discussed by HDL Forum Editors Professors Kerry-Anne Rye and John Chapman.

 Silva RAGD, Huang R, Morris J et al. Structure of apolipoprotein A-I in spherical high density lipoproteins of different sizes. Proc Natl Acad Sci 2008;105:12176-81.

While there is clear recognition of the importance of HDL cholesterol to cardiovascular disease risk, there is somewhat limited understanding of the structure of HDL and its relevance to metabolism and function.  In particular, little is known about the structure of apolipoprotein A-I (apoA-I) in spherical HDL particles, compared with better studied discoidal HDL. ApoA-I is the main protein in HDL, accounting for about 70% of the total HDL protein. ApoA-I can be generally regarded as the ‘glue’ holding most HDL particles together. ApoA-I is involved in promoting the efflux of cholesterol from cells and also has anti-oxidant and anti-inflammatory properties.

 In the current study, the authors studied spherical and discoidal reconstituted HDL (rHDL) particles of comparable diameters (approximately 79-80Å and 93-96Å). The spherical rHDL were prepared using methods that were as physiological as possible, by incubating discoidal rHDL with low density lipoproteins and lecithin:cholesterol transferase, (LCAT), the enzyme responsible for generating almost all of the cholesteryl esters in plasma (Figure 1). 

 Figure 1. Preparation of spherical reconstituted HDL

 

Using cross-linking chemistry and mass spectrometry, the authors showed that the structural organisation of apoA-I was similar in the HDL discs and spheres, irrespective of diameter. Even in HDL spheres of 93Å, which contained three molecules of apoA-I per particle (compared with HDL discs which contained two molecules), a similar structure was demonstrated.  These data suggest that apoA-I adopts the same structural framework in all HDL particles.

 The authors also showed that cross-linking patterns in spherical HDL (93Å) were consistent with those demonstrated in HDL3 particles isolated from human plasma, reinforcing the clinical relevance of their findings using reconstituted particles to native HDL.

Based on their findings, the authors compared various models (Figure 2) but proposed a trefoil molecular model for apoA-I structure in spherical HDL (D, Figure 2), given the similarity of the cross-linking patterns in HDL discs (with two apoA-I molecules) and HDL spheres (with three apoA-I molecules). This model allows for symmetrical intercalation of additional apoA-I molecules (as human HDL particles can contain between 2 and 4 molecules of apoA-I), as well as optimal interactions between apoA-I and proteins that associate with HDL. This structure also enables spherical HDL to modulate their diameter in response to variations in their lipid cargo.

 Figure 2. Proposed trefoil model for apoA-I in spherical HDL

The red, green and blue indicate different apoA-I molecules within the spherical HDL

 

 

In their conclusions, the authors indicate that this trefoil model provides a foundation for further experimentation aimed at understanding how apoA-I structure influences HDL function and metabolism.

 

 

 


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