Determination of the Dynamic Structures of Nacent Discoidal High-Density Lipoprotein (HDL) Bound to Lecithin Cholesterol Acyltransferase (LCAT) and Paraoxonase 1 (PON1)

Abstract

The relative levels of plasma cholesterol in different lipoproteins are the major indicator for CVD and related diseases. Nascent discoidal HDL particles, which are then converted to spherical mature HDL by lecithin-cholesterol acyltransferase (LCAT), are integral in reverse cholesterol transport. Detailed knowledge of HDL structure is key to understanding its molecular mechanisms, including how Paraoxynase 1 (PON1) associates with the phospholipid surface of HDL helping prevent oxidation. Despite public interest in HDL structure related function, their highly dynamic nature has prevented precise structural determinations for nearly half a century. Here, we used our recently developed individual particle electron tomography (IPET) technique to study each individual complex of HDL-LCAT. The 3D reconstructions show, i) LCAT associates with HDL along a proposed mobile region of the apoA-1 backbone (res ∼122-142), where both monomers overlap antiparallel along the discoidal edge of HDL; ii) PON1 interacts with HDL through its hydrophobic tail, which binds into the phospholipid surface, and loosely associates with apoA-1. The structure provides novel information for modeling nascent discoidal HDL and further reveals the first view of HDL structural dynamics in three-dimensions. This result will benefit public knowledge and pharmaceutical drug design to control plasma HDL cholesterol level.