7 Mar 2024
Job Information
- Organisation/Company
Inserm U1242 Oncogenesis, Stress, Signaling- Research Field
Chemistry » Biochemistry
Biological sciences » Biology
Chemistry- Researcher Profile
Recognised Researcher (R2)
Leading Researcher (R4)
First Stage Researcher (R1)
Established Researcher (R3)- Country
France- Application Deadline
14 Apr 2024 - 22:00 (UTC)- Type of Contract
Temporary- Job Status
Full-time- Offer Starting Date
1 Oct 2024- Is the job funded through the EU Research Framework Programme?
Not funded by an EU programme- Is the Job related to staff position within a Research Infrastructure?
No
Offer Description
Mission – We are looking for a skilled and highly motivated PhD candidate with a degree in chemical biology, biochemistry, biophysics, molecular biology or related fields to unravel the molecular mechanisms of a receptor kinase signaling associated with human health and diseases.
Context – Cellular stress induced by the abnormal accumulation of improperly folded proteins in the endoplasmic reticulum (ER) is emerging as a major actor in disease development and an appealing actionable target. ER stress levels are under constant surveillance by the unfolded protein response (UPR), a major adaptive mechanism that lies at the core of cellular homeostasis and is responsible for cellular life-or-death decisions. The Inositol-requiring enzyme 1 (IRE1), the most evolutionary conserved UPR transducer, is an ER-resident transmembrane protein with a cytosolic dual kinase/RNase activity controlling pro-survival or pro-death signals. Yet, despite >20 years of investigations, the precise molecular mechanisms by which IRE1 is activated and exerts its catalytic and scaffolding functions still remain unclear and a subject of debate.
PhD project - This PhD project is part of the Agence Nationale de la Recherche (ANR)-funded INSPIRE1 program, which aims at deciphering the molecular mechanisms of IRE1 activation through a unique and novel prism at the interface of chemical biology, supramolecular chemistry and structural biology. More specifically, you will focus on using a programmable synthetic platform based on DNA structures (e.g. DNA origami) to control the nanoscale organization and nature of different IRE1 complexes, including their oligomeric state and degree of phosphorylation.
This approach will enable you to:
1 - Identify the complexes responsible for the different activity levels of IRE1 RNase function.
2 - Characterize their substrate specificity.
3 - Obtain structural information on these different complexes by CryoEM.
Main activities –
• Molecular biology (design and conception of plasmids for protein expression).
• Protein expression in prokaryotic (bacteria) and eukaryotic (insect and human) cells.
• Protein engineering, bioconjugation, purification (affinity & SEC).
• Structural characterization of protein-DNA conjugates (AFM, CryoEM).
• Functional and biophysical characterization in vitro of enzymatic activities (kinase & RNase), substrate specificity (RT-qPCR), protein-protein interactions (ITC, fluorescent spectroscopy, SPR, BLI and others).
National and international collaborations
• Dr Pierre Maisonneuve, Structural Biology, Université de Bordeaux, France.
• Pr. Luc Brunsveld, DNA origami and protein assemblies, Eindhoven University of Technology, Pays-Bas.
• Pr. Leif A. Eriksson, molecular modeling of protein complexes, University of Gothenburg, Sweden.
Depending on the advancements of the project, a secondment in any of these research groups during the PhD is possible, and a strong command of English is therefore needed.
Recent references from the group
1. Mahdizadeh, S. J.; Grandén, J.; Pelizzari-Raymundo, D.; Guillory, X.; Carlesso, A.; Chevet, E.; Eriksson, L. A. Different Binding Modalities of Quercetin to Inositol-Requiring Enzyme 1 of S. Cerevisiae and Human Lead to Opposite Regulation. Commun. Chem. 2024, 7 (1), 1–12. https://doi.org/10.1038/s42004-023-01092-0 .
2. Pelizzari-Raymundo, D.; Doultsinos, D.; Pineau, R.; Sauzay, C.; Koutsandreas, T.; Langlais, T.; Carlesso, A.; Gkotsi, E.; Negroni, L.; Avril, T.; Chatziioannou, A.; Chevet, E.; Eriksson, L. A.; Guillory, X. A Novel IRE1 Kinase Inhibitor for Adjuvant Glioblastoma Treatment. iScience 2023, 106687. https://doi.org/10.1016/j.isci.2023.106687 .
3. Obacz, J.; Archambeau, J.; Lafont, E.; Nivet, M.; Martin, S.; Aubry, M.; Voutetakis, K.; Pineau, R.; Boniface, R.; Sicari, D.; Pelizzari-Raymundo, D.; Ghukasyan, G.; McGrath, E.; Vlachavas, E.-I.; Le Gallo, M.; Le Reste, P. J.; Barroso, K.; Fainsod-Levi, T.; Obiedat, A.; Granot, Z.; Tirosh, B.; Samal, J.; Pandit, A.; Négroni, L.; Soriano, N.; Monnier, A.; Mosser, J.; Chatziioannou, A.; Quillien, V.; Chevet, E.; Avril, T. IRE1 Endoribonuclease Signaling Promotes Myeloid Cell Infiltration in Glioblastoma. Neuro-Oncology 2023, noad256. https://doi.org/10.1093/neuonc/noad256 .
4. Langlais, T.; Pelizzari-Raymundo, D.; Mahdizadeh, S. J.; Gouault, N.; Carreaux, F.; Chevet, E.; Eriksson, L. A.; Guillory, X. Structural and Molecular Bases to IRE1 Activity Modulation. Biochemical Journal 2021, 478 (15), 2953–2975. https://doi.org/10.1042/BCJ20200919 .
Funding category: Contrat doctoral
Contrat doctoral ordinaire
PHD Country: France
Requirements
Specific Requirements
Applicant profile – We encourage applications from highly motivated students from the national and international community with a background in chemical biology, biochemistry, biophysics, molecular biology, or other life sciences and with outstanding qualifications. Candidates should be recent graduates from Universities or Engineering Schools with a Master’s Degree (or equivalent) or should expect to receive their degree before September 2024.
Previous experiences in the laboratory on technics related to the PhD project is an advantage and knowledge of bioconjugation or structural biology is a plus.
The candidate must possess a strong scientific rigor and a keen interest and motivation for interdisciplinary projects, along with autonomy, critical thinking and the ability to work as part of a team.
Additional Information
Work Location(s)
- Number of offers available
- 1
- Company/Institute
- Inserm U1242 Oncogenesis, Stress, Signaling
- Country
- France
- City
- Rennes
- Geofield
Where to apply
- Website
https://www.abg.asso.fr/fr/candidatOffres/show/id_offre/120936
Contact
- Website
http://oss-clcc-rennes.com/
STATUS: EXPIRED