Structural Biology

Biography

Stefan Bibow since Jan 2017 is a project leader at the Biozentrum of the University of Basel (as an Ambizione fellow). From Sep 2012 – Dec 2012   was a scientific visitor at the Salk Institute, La Jolla, USA. He was a Postdoctoral fellow from Jan 2012 – Dec 2016 at ETH Zurich, Switzerland. He completed his PhD at Max Planck Institute for Biophysical Chemistry, Göttingen, Germany in August 2011. He did his Diploma in Biophysics, Humboldt University of Berlin, Germany in May 2007. He has done his Matriculation for Biophysics at the Humboldt University of Berlin in October 2001.    

Abstract

High-density lipoprotein particles (HDLs) are transport containers in the circulatory system that receive cellular cholesterol and lipids destined for the liver and other lipoprotein particles. Because low levels of HDL-cholesterol often indicate an increased risk for cardiovascular diseases, HDL particles are considered as important pharmacological targets for therapeutic strategies. Mature spherical HDLs develop from lipid-free apolipoprotein apoA-I through the formation of intermediate discoidal HDL particles which are the primary acceptors of cellular cholesterol. Although of high biophysical and medical importance heterogeneity in density, size, shape, as well as protein and lipid composition prohibited a detailed molecular and structural description of discoidal HDL particles. Here, we present the three-dimensional solution structure of reconstituted discoidal HDL (rdHDL) particles by combining nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR) and transmission electron microscopy (TEM) data. By using amino acid selective labeling, methyl labeling, Lipid-PREs and long-range EPR data we found that rdHDL particles are composed of two helical apoA-I molecules that dimerise in an anti-parallel fashion to form a double belt around a lipid bilayer patch. The integrity of this unique structure is maintained by up to 28 salt bridges and an unusual zipper-like pattern of cation-π interactions between helices 4 and 6. In order to accommodate a hydrophobic interior a gross ‘right to right’ rotation of the helices upon lipidation is necessary. The structure relevant in our understanding of HDL-biology and metabolism reflects thereby the beauty and complexity of this type of biological shuttling container that is able to hold a fluid lipid/cholesterol interior at a protein lipid ratio of 1:50.