Conformational and aggregation properties of the 1-93 fragment of apolipoprotein A-I

Summary, in English

Several disease-linked mutations of apolipoprotein A-I, the major protein in high-density lipoprotein (HDL), are known to be amyloidogenic, and the fibrils often contain N-terminal fragments of the protein. Here, we present a combined computational and experimental study of the fibril-associated disordered 1-93 fragment of this protein, in wild-type and mutated (G26R, S36A, K40L, W50R) forms. In atomic-level Monte Carlo simulations of the free monomer, validated by circular dichroism spectroscopy, we observe changes in the position-dependent β-strand probability induced by mutations. We find that these conformational shifts match well with the effects of these mutations in thioflavin T fluorescence and transmission electron microscopy experiments. Together, our results point to molecular mechanisms that may have a key role in disease-linked aggregation of apolipoprotein A-I.

• Author: Jitka Petrlova; Arnab Bhattacherjee; Wouter Boomsma; Stefan Wallin; Jens O Lagerstedt; Anders Irbäck
• Department/s: Dermatology and Venereology (Lund); Computational Biology and Biological Physics - Undergoing reorganization; Medical Protein Science
• Publishing year: 2014-11
• Language: English
• Pages: 71-1559
• Publication/Series: Protein Science
• Volume: 23
• Issue: 11
• Links: http://dx.doi.org/10.1002/pro.2534
• Document type: Journal article
• Publisher: The Protein Society
• Topic: Other Physics Topics; Biophysics; Physical Chemistry
• Keywords: Amyloid; Apolipoprotein A-I; Circular Dichroism; Intrinsically Disordered Proteins; Molecular Dynamics Simulation; Protein Structure, Secondary
• Status: Published
• Research group: Medical Protein Science
• ISBN/ISSN/Other: ISSN: 1469-896X