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Liposomes, Exosomes, and Virosomes: From Modeling Complex
Membrane Processes to Medical Diagnostics and Drug Delivery
Wednesday Speaker Abstracts
34
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