Biophysical Society Thematic Meeting | Ascona, Switzerland

Liposomes, Exosomes, and Virosomes: From Modeling Complex Membrane Processes to Medical Diagnostics and Drug Delivery

Wednesday Speaker Abstracts

The Role of Membranes During Polyglutamine Self Aggregation of Huntingtin Burkhard Bechinger 1 , Nicole Harmouche 1 , Arnaud Marquette 1 , Evgeniy Salnikov 1 , Louic Vermeer 1 , Matthias Michalek 1,3 , Rabia Sarroukh 2 , Vincent Raussens 2 , Erik Goormaghtigh 2 . 1 University of Strasbourg/CNRS, Strasbourg, Alsace, France, 2 Free University of Brussels, Brussels, Belgium, 3 Univerisity of Kiel, Kiel, Germany. The accumulation of aggregated protein is a typical hallmark of many human degenerative disorders, amongst which is Huntington's disease. Misfolding of the amyloidogenic proteins give rise to self-assembled aggregates. The huntingtin protein is characterized by a segment of consecutive glutamines (Qn), responsible for its fibrillation. It has been demonstrated that the 17 residue N-terminal domain of the protein, located upstream of its polyglutamine tract, strongly influences its aggregation behavior, and thereby the correlated development of the disease. We have shown that this Htt-17 domain can act as a reversible membrane anchor when at the same time it markedly increases polyglutamine aggregation rates. Here we characterize in quantitative detail how cross-talk between Htt17, the polyglutamine tract and liposomes strongly affects polyQ aggregation kinetics. Furthermore, we investigated membrane interactions, structure, topology and aggregation of Htt- 17-polyQ in great detail. The structural transitions of Htt17 upon membrane-association result in an in-plane aligned stable α-helical conformation. The membrane binding of Htt17 was analyzed and is strongly dependent on lipid composition, whereas the helical tilt angle is constant in all investigated membranes. The activity of the Htt17 membrane anchor is pivotal in bringing together the polyglutamine domains, facilitating their oligomerization into β-sheet fibrils. Our study shows how the membrane interactions of protein domains influences the supramolecular organization of amino acid polymers in a complex chemical environment and more specifically the role of the membrane interface in the folding and amyloid formation of polyglutamines. Such quantitative biophysical and structural data may also help to successfully design new therapeutic concepts and molecules targeting the N-terminal regions of huntingtin as well as proteins of other polyglutamine-related diseases.

Folding Steps of Single Polypeptides into Membrane Proteins

Daniel Müller Eidgenössische Techniche Hochschule Zürich, Zürich, Switzerland

No Abstract

34