Thesis supervisor: Zoltán Varga
Location of studies (in Hungarian): Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen Abbreviation of location of studies: DEBSI
Description of the research topic:
The voltage-gated proton channel Hv1 is found in many cell types: macrophages, neutrophils, B-lymphocytes, osteoclasts, skeletal muscle cells, as well as in various cancer cells. Hv1 is involved in numerous signaling pathways via the regulation of the intracellular pH. It acts as a perfect H+ valve, extruding protons during cytoplasmic acidification without energy expenditure. Its best known function is to stabilize the pH and the membrane potential of phagocytes during the production of reactive oxygen species (ROS). Its function is linked to diseases associated with excessive ROS production and to tumor invasiveness.
Structurally, Hv1 is like a single voltage-sensing domain (VSD) of “classical” voltage-gated ion channels, consisting of 4 transmembrane helices, but it lacks the pore domain. Thus, in Hv1, proton selective conduction across the membrane occurs through the VSD itself via a hydrogen-bonded chain formed by water molecules and amino acid side chains. Hv1 channels function as dimers, in which each protomer can conduct on its own, but gating is cooperative.
Our main goals in the project are the following:
1. Understanding the conformational changes occurring during voltage-dependent gating. What motions do the four helices go through to form the conduction pathway?
2. Elucidating the details of the interaction of Hv1 with its potent physiological activator, arachidonic acid (AA). We wish to identify its site and mechanism of action.
3. Identifying new peptide and small molecule inhibitors of Hv1 and determining their sites and mechanisms of action, as well as their selectivity over other channels.
Required language skills: English intermediate level Number of students who can be accepted: 2
Deadline for application: 2021-11-15
2024. IV. 17. ODT ülés Az ODT következő ülésére 2024. június 14-én, pénteken 10.00 órakor kerül sor a Semmelweis Egyetem Szenátusi termében (Bp. Üllői út 26. I. emelet).
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