'Good' Cholesterol Comes Into Focus

High-density lipoprotein—the so-called good cholesterol—plays an important role in reducing the risk of heart disease. Despite its importance, all structural information has come from synthetic HDL particles. Now, biochemists at the University of Cincinnati have obtained the first structural information on HDL isolated from human plasma (Nat. Struct. Molec. Biol., DOI: 10.1038/nsmb.2028).

An understanding of HDL's structural organization "will be highly significant for future development of drugs affecting the anti-inflammatory, antioxidant, and antiatherogenic functions of HDL that could lead to new approaches to preventing and reversing coronary heart disease," says Jere P. Segrest, a researcher studying lipoprotein structure at the University of Alabama, Birmingham.

HDL particles aren't suited to high-resolution methods like X-ray crystallography or NMR. W. Sean Davidson and coworkers instead turned to mass spectrometric analysis of cross-links between lysines to obtain distance constraints they could use to model the most abundant protein in HDL particles, apolipoprotein A-1 (ApoA-1).

Synthetic HDL particles—which are built in the lab from HDL's protein parts—typically contain only three ApoA-1 chains, but the HDL particles that Davidson and coworkers isolated were larger, containing four or five chains. The cross-linking patterns, which are similar regardless of the number of protein chains, suggest that ApoA-1 adopts a symmetric cagelike structure. Size differences between particles with the same number of chains appear to be due to the twisting of protein chains while maintaining the same contacts.

"Surprisingly and importantly, the chemical cross-linking and mass spectrometry results show that ApoA-1 maintains distinct intermolecular contacts regardless of HDL particle size and shape," says Michael C. Phillips, an HDL researcher at Children's Hospital of Philadelphia.

Even such low-resolution structures could help scientists figure out good places to mutate on the protein to figure out how it functions, Davidson says. "That's going to take us a long way toward understanding how HDL is protective against cardiovascular disease and will help take us to the next step of designing ways to mimic it."