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Reference : UMR5672-FABMON-004
Workplace : LYON 07
Date of publication : Monday, October 4, 2021
Scientific Responsible name : Fabien Montel
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 1 November 2021
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly
Description of the thesis topic
Biological pores are essential actors in cell function. For example, ion channels are responsible for the transmission of neuronal information while the nuclear pore has an essential role in the regulation of gene expression [1,2]. Their dysfunction is implicated in acute or chronic diseases (cancer, Charcot disease) and viral infections (HIV, HBV). One of their most remarkable properties is the selectivity of these nanofluidic channels and their ability to select from the complex mixture that is the cellular medium only the molecule that must be transported and the direction of this transport.
In the case of pores involved in the transport of macromolecules such as the nuclear pore (Figure left) which regulates exchanges between the nucleus and the cytoplasm, it has been shown that selectively transported species carry a peptide signal (NLS, nuclear localization signal) which induces a higher affinity for a transporter and ultimately the central channel of the nuclear pore .
The wide variety of proteins with significant affinity for the nuclear pore raises the question of the robustness of this mechanism. For example, how sensitive is the phenomenon to changes in the concentration of one of the competitors on the material flow of a particular species? Surprisingly, recent theoretical work has shown that a molecule can exhibit a higher translocation rate in the presence of competing molecules and that there is a flux optimum for a particular affinity [3,4].
In this project we propose to use a nuclear pore mimetic approach to measure the effect of multi-species competition at the pore entrance on the selectivity and flux of molecules through the pore. We will use artificial functionalized nanoporous membranes to reproduce the essential elements of this phenomenon. We will then measure the link between affinity for the nanopore and the ability to maintain a high flux of material through the pore. The measurement of the translocation frequency will be performed at the single molecule scale by Zero Mode waveguide, a highly parallelized optical near-field method developed in the team (Figure right, [5,6]). Our results will allow the construction of a quantitative and detailed representation of the impact of competition between several actors at the pore entrance on the translocation energy landscape across the nanopore.
1. The nuclear pore complex and nuclear transport. Wente SR, Rout MP. Cold Spring Harb Perspect Biol. 2010 Oct;2(10):a000562.
2. Nuclear pore complex plasticity during developmental process as revealed by super-resolution microscopy. Selles J , Penrad-Mobayed M, Guillaume C, Fuger A, Auvray L, Faklaris O, Montel F. Scientific Reports 7 (14732) NOV 7 2017
3. Enhancement of transport selectivity through nano-channels by non-specific competition. Zilman A, Di Talia S, Jovanovic-Talisman T, Chait BT, Rout MP, Magnasco MO. PLoS Comput Biol. 2010 Jun 10;6(6):e1000804.
4. Efficiency, selectivity, and robustness of nucleocytoplasmic transport. Zilman A, Di Talia S, Chait BT, Rout MP, Magnasco MO. PLoS Comput Biol. 2007 Jul;3(7):e125.
5. Zero-mode waveguide detection of flow-driven DNA translocation through nanopores. Auger T, Mathé J, Viasnoff V, Charron G, Di Meglio JM, Auvray L, Montel F. Phys Rev Lett. 2014 Jul 11;113(2):028302.
6. Zero-Mode Waveguide Detection of DNA Translocation Through FIB-organised Arrays of Engineered Nanopores. Auger T, Bourhis E, Donnez J, Durnez A, Di Meglio J-M, Auvray L, Montel F, Yates J, Gierak J. Microelectronic Engineering 187, 90-94 (2018)
Activities of the Physics Laboratory cover various fields, from statistical physics to hydrodynamic turbulence, including also mathematical physics and signal processing but also soft and condensed matter. This multidisciplinary approach is particularly fostered by the strong association with the physics teaching activities at ENS de Lyon.
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