Three-dimensional structure of low density lipoproteins by electron cryomicroscopy

Three-dimensional structure of low density lipoproteins by electron cryomicroscopy

^*Verna and Marrs McLean Department of Biochemistry and ^§Department of Medicine, Baylor College of Medicine, Houston, TX 77030; ^‖Cornell University Medical College, New York, NY 10021; and ^¶Valentis, Inc., 8301 New Trails Drive, The Woodlands, TX 77381

Communicated by Salih J. Wakil, Baylor College of Medicine, Houston, TX (received for review December 29, 1998)

Abstract

Human low density lipoproteins (LDL) are the major cholesterol carriers in the blood. Elevated concentration of LDL is a major risk factor for atherosclerotic disease. Purified LDL particles appear heterogeneous in images obtained with a 400-kV electron cryomicroscope. Using multivariate statistical and cluster analyses, an ensemble of randomly oriented particle images has been subdivided into homogeneous subpopulations, and the largest subset was used for three-dimensional reconstruction. In contrast to the general belief that below the lipid phase-transition temperature (30°C) LDL are quasi-spherical microemulsion particles with a radially layered core-shell organization, our three-dimensional map shows that LDL have a well-defined and stable organization. Particles consist of a higher-density outer shell and lower-density inner lamellae-like layers that divide the core into compartments. The outer shell consists of apolipoprotein B-100, phospholipids, and some free cholesterol.

Footnotes

↵ † Present address: Department of Biochemistry, Imperial College of Science, Medicine and Technology, London SW7 2AY, U.K.
↵ ‡ To whom reprint requests should be addressed. e-mail: wah{at}bcm.tmc.edu.
ABBREVIATIONS:

LDL,

low density lipoprotein;

3D,

three dimensional