Structural investigation of the human Low-Density Lipoprotein
Tamás Földes, Madalena Branco, Maria Bacia, Ambroise Desfosses
Cardiovascular disease accounts for 32% of deaths worldwide and is considered the leading cause of premature mortality. For risk assessment and treatment, modern guidelines indicate serum low-density lipoprotein (LDL) cholesterol levels as the primary target. Instrumental in the metabolism and homeostasis of cholesterol and lipid transportation, LDLs are complex 17-28 nm nanoparticles comprised of a phospholipid membrane surface and a lipid core, wrapped by the amphiphilic apolipoprotein B-100. Solving the LDL structure at atomic resolution is particularly challenging due to their heterogeneous composition and flexibility.
Our consortium combines experimental techniques and molecular modelling to get insights into the structure of LDL. The experimental approaches provide data on specific individual aspects, and the molecular modelling integrates them into a comprehensive and dynamic overall model. While our first cryo-EM analysis revealed the LDL shape and core organisation, we are now collecting new data and using more intricate image analysis to achieve higher resolution. Additional structural information is being gained from neutron and X-ray scattering experiments, performed in ILL and ESRF, that can capture structural motifs at both larger and smaller scales. Our new computational approach, using both AlphaFold and classical molecular dynamics at a coarse-grain level, heavily relies on all these findings to construct a molecular model that is able to reflect the LDL structure and dynamics.
Collaborations :
– Judith Peters, ILL/LiPhy, Grenoble
– Karin Kornmüller, Medical University of Graz, Austria