Study uncovers structure of ‘good’ HDL cholesterol

By Nathan Gray

- Last updated on GMT

The structure of high-density lipoproteins (HDL) from human plasma has been modelled for the first time. Researchers say the finding may help to explain how HDL protects against cardiovascular diseases.

The study, published in the Nature Structural & Molecular Biology​, found that most of the HDL particles circulating in human plasma are very similar in structure, with researchers reporting that the surface of HDL is “dominated”​ by the presence of the cardio- protective protein apolipoprotein A-I (apoA-I).

The research team, led by scientists at the University of Cincinnati, used a series of spectroscopic and mass spectrometric techniques to study the structure of HDL – finding that the apoA-I proteins form a cage-like structure to encapsulate HDLs lipid cargo.

The authors said that their findings may help to explain how HDL (often referred to as ‘good cholesterol’) protects against cardiovascular diseases, including heart attack and stroke.

“Our demonstration that apoA-I overwhelmingly dominates the surface of these HDL particles may provide clues to how other HDL-associated proteins interact with these particles,” ​said the authors, led by W. Sean Davidson, professor in the department of pathology and laboratory medicine, at the University of Cincinnati, USA.

“This work presents the first detailed models of human plasma HDL and has important implications for understanding key interactions in plasma that modulate its protective functions in the context of cardiovascular disease,”​ said Davidson.

‘Good’ cholesterol

High-density lipoproteins (HDLs) cholesterol are small molecules of protein and fat that transport fat to specific locations within the body and assist in cholesterol transport to the liver. They have been shown to offer protection from cardiovascular diseases.

“Unfortunately, we've known very little about the molecular details that explain HDL's protective effects …A major reason for this is an almost complete lack of understanding of HDL's structure and how it interacts with other important plasma factors,”​ said Prof. Davidson.

Previous studies of synthetic HDL have suggested that the apolipoprotein A-I (apoA-I protein in HDL, plays a key role in its cardio-protective, anti-inflammatory, and anti-oxidative properties.

Prof. Davidson explained that that previous studies have solely focused on looking at the structure of synthetic HDL; he explained that “by isolating human HDL, we were able to focus on the broad range of HDL particles actually circulating in humans.”

Study details

In determining the structure of HDL, Davidson and his team were able to conclude that the majority of physiological interactions occurring with HDL – including its twisting movements – occur at the particle surface, which is dominated by the cardio protective protein apolipoprotein A-I.

They explained that HDL had previously been shown to contain between 35 and 50 minor proteins – in addition to apoA-I. However the new study revealed that apoA-I accounted for the majority of HDLs surface.

“The presumption has been that these proteins associate with the phos­pholipid surface to coexist with apoA-I​. However, it is clear from the models and our composition calculations that about 85 percent of the …​[HDL] particle surface is covered by apoA-I,”

“It is thus difficult to imagine how other proteins can find room to bind,” ​said the authors.

The researchers reported that as the primary protein, apoA-I adopts a structural framework in human plasma HDL that “closely mirrors that in synthetic HDL.”

The authors explained that their models suggest that HDL particle size “is modulated by means of a twisting motion of the resident apoA-I molecules.”

“This understanding offers insights into how apoA-I structure modulates HDL function and its interactions with other apolipoproteins,”​ they explained.

Davidson suggested that the monopolization of HDL’s surface by apolipoprotein A-I means that other proteins have very little opportunity room to bind with HDL, and thus have to interact with the protein itself – explaining why apo A-I plays a dominant role in HDL function and its protective effects.

Source: Nature Structural & Molecular Biology
Published online ahead of print, doi: 10.1038/nsmb.2028
“Apolipoprotein A-I structural organization in high-density lipoproteins isolated from human plasma”
Authors: R. Huang, R.A.G.D. Silva, W.G. Jerome, A. Kontush, et al

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