Jens Lagerstedt
PhD, Docent
Experimental Medical Science, Faculty of Medicine, Lund University
Tel: +46(0)46-2227266
E-mail: Jens.Lagerstedt@med.lu.se
Website: http://www.med.lu.se/english/expmed/research/medical_protein_science
Abstract
Apolipoprotein A-I (apoA-I) is the main protein component of high-density lipoprotein (HDL). The central role of the apoA-I protein is in the so-called reverse cholesterol transport pathway where excess cholesterol is removed from the vascular wall, and transported back to the liver, and thereby provide an atheroprotective effect. A positive influence of apoA-I/HDL on glucose control, with potential implications in the prevention and treatment of diabetes, have also been demonstrated. These features of the apoA-I protein have spurred large interests in exploring the translational medicine potential in cardiovascular disease and diabetes.
Much attention has also been given to the structural and functional properties of the apoA-I protein, both in the apo-state and in the HDL-bound states. However, despite apoA-I is a relatively small protein (the mature protein is 243 amino acids), it is highly abundant in blood (about 40-60 mg/dl apoA-I) and can be easily produced in large amounts as recombinant protein from heterologous production systems, the high structure plasticity and large number of hydrophobic amino acids of the apoA-I have challenged classical X-ray crystallography approaches. Complementary approaches such as EPR spectroscopy, Synchrotron Radiation Circular Dichroism and CryoEM have therefore also been used.
In addition to native apoA-I, several human variants of apoA-I that affect the in vivo function of the protein have been described. Such ApoA-I hereditary systemic amyloidosis is a rare, autosomal dominant, late onset disease caused by specific mutations in the APOA1 gene, leading to misfolding of the proteins and the aggregation in amyloid fibrils. Interestingly, the localization of the mutations in the ApoA-I protein sequence seems to direct protein aggregation in specific organs, either to the liver/kidney or heart/skin.
The structural features of native and amyloidogenic apoA-I and how they relate to protein function, as well as their in vivo functionality, will be discussed.
Recent data from a different project area where Synchrotron Xray Fluorescence Imaging is used to study metal (Zn) content in insulin-producing pancreatic beta cells in diabetes will also be briefly discussed.
