The Molecular Architecture of Human Low Density Lipoprotein and Bound Receptor Revealed by Electron Cryo-Microscopy

Abstract

An elevated plasma level of low density lipoprotein (LDL)-cholesterol is a well-documented risk factor for cardiovascular disease. LDL transfers cholesterol from plasma to liver cells via the LDL receptor (LDLr). LDL is heterogeneous in composition, shape, size, density and charge and is difficult for structural study by X-ray crystallization and NMR. Here, we used electron cryo-microscopy (Cryo-EM) and image analysis to study the structures of LDL and LDL•LDLr complex. We found 1) the reconstructed LDL embedded in vitreous ice is approximated a flattened ellipsoid with planar opposing faces. 2) The reconstructed map of the LDL•LDLr complex was similar to that of LDL in shape and size, but with a ∼35-45 A protrusion attached on the surface. The protrusion matched in size to the LDL receptor beta-propeller domain. 3) The internal density distribution of LDL showed a liquid crystalline core containing three similarly sized internal high density “isthmi”. 4) The LDL high-density regions that correspond to the apo B-100 appear as a pair of paddles connected at one end of the particle by a linker region with three separate long semicircular “fingers” extending from each edge of the linker region to wrap around the particle. These results allowed us to propose an architecture model of LDL, in which the core CE molecules arranged in stacks with their sterol moieties side-by-side in the higher density regions and the fatty acyl chains extending from either side. These stacks of acyl chains in the CE core are directed outward towards the amphipathic beta-sheet domains on the top and bottom faces of the particle and are surrounded by a semicircle of flexible amphipathic alpha-helix rich domains, which is important to maintaining the structural integrity, and thus functionality, of normal LDL.