Objective
One third of the cell proteome utilizes the secretory pathway for entrance into the endoplasmic reticulum (ER). However, the insertion of nascent proteins into or their translocation across the ER membrane, their maturation and assembly to oligomeric complexes and their degradation are very basic cellular processes of which we largely lack an integrative structural insight.
I propose to use Cryo Electron Tomography (CET) to unravel the molecular mechanism of the biogenesis and degradation of Major Histocompatibility Complex-I (MHC-I) as a model substrate in situ. MHC-I are critical for immune responses to viruses and tumors. They are hetero-trimeric complexes formed by a light chain, a heavy chain and a variable cellular or microbial peptide. MHC-I folding is assisted by the chaperones ERp57 and calnexin at the ER membrane, where it assembles co-translationally, stabilized by tapasin. Once loaded with a peptide, MHC-I is exported to the cell surface for recognition by CD8+ T-cells. However, some viral immunoevasins like the human cytomegalovirus (HCMV) proteins US2 and US11 trigger the ER-Associated Degradation (ERAD) of MHC-I. I will combine data from CET, cross linking mass spectrometry (XL-MS) and in vitro functional assays on eukaryotic cellular and microsomal cell-free systems to provide an integrated picture of the complexes transiently involved in these processes.
This work will make great contributions to our molecular understanding of cellular proteostasis and possibly provide novel molecular targets addressing diseases associated with ER stress.
The proposed project will extend my knowledge from protein X-ray crystallography to the study of more complex molecular assemblies in association with membranes at larger length scales – ultimately the cell.
Taken together, this project represents a unique opportunity to start blooming in my career as an independent researcher with a strong european network, and become a leader in the scientific community.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins proteomics
- natural sciences biological sciences microbiology virology
- natural sciences earth and related environmental sciences geology mineralogy crystallography
- medical and health sciences basic medicine immunology
- natural sciences chemical sciences analytical chemistry mass spectrometry
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions
MAIN PROGRAMME
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H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
MSCA-IF-EF-ST - Standard EF
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) H2020-MSCA-IF-2017
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
3584 CS Utrecht
Netherlands
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.