Structural and Dynamical Exploration of Low Density Lipoprotein – STRUDEL

Wider research context: Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Elevated blood cholesterol levels are a major risk factor in the development of CVDs. Low density lipoproteins (LDL) direct the transport of cholesterol and fat to peripheral tissues and cells. Due to this function, LDL and its protein moiety apolipoprotein B-100 (apo B-100) are major key-players in the development of CVDs. LDL’s role in physiology but also in pathology is linked to its structure.

Hypothesis: We hypothesize that changes due to pathologies in the chemical composition of LDL are reflected in the structure of LDL and its protein moiety apo B-100. Thus, a structural description with near atomic resolution, in combination with attributed dynamical features will help to correlate structure to function - and accordingly to dysfunction.

Approach: To obtain new models of LDL and apo B-100 with an unprecedented level of detail we will pursue two individual paths that will converge: LDL will be investigated, and independently its sole protein moiety apo B-100 in a lipid-free detergent-stabilized form. To access their structures we will combine state-of-the-art cryo-EM techniques and SAXS. In addition, neutron scattering methods will be complemented by coarse-grain simulations to describe the dynamical features of LDL in its entirety, as well as different domains of apo B-100. All methods will be applied not only on normolipidemic LDL and/or its subfractions, but also on triglyceride-rich and oxidized LDL to mimic pathologic conditions as found in hyperlipidaemia or in atherosclerotic plaques.

Level of originality: Rapid technological progress within the last few years in cryo-EM instrumentation rendered it possible to look at structures with a level of detail that has never been achievable before. Here we combine the best state-of-the-art instrumentation, with one of the most challenging proteins. Apo B-100 is one of the largest monomeric proteins known, and due to its amphiphilic nature has only in a few studies been investigated out of its lipidic environment. The link between the various approaches is performed through molecular dynamics simulations. The success of this project will have an impact on how we understand the pathological progression of CVDs.

Primary researchers involved: The project team comprises 5 scientists with proven excellence and competence in their research fields. Karin Kornmüller and Ruth Prassl from the Medical University of Graz, Austria, are experts in lipoprotein research, X-ray scattering techniques, and translational biophysics. Judith Peters from the University Grenoble Alpes, France, is expert in molecular dynamics and neutron scattering techniques. Ambroise Desfosses (Institut de Biologie Structurale, Grenoble, France) and Daouda Traore (Univ. of Keele, UK, and Institut Laue Langevin, Grenoble, France) are both experts in cryo-EM methods and data analysis.