Project description
Safeguarding the nuclear envelope under mechanical stress
The nuclear envelope (NE) protects the cell’s genetic material and regulates communication between the nucleus and cytoplasm through nuclear pore complexes (NPCs). These large protein assemblies expand under mechanical tension, but how they avoid disintegration remains unknown. Nup210, a nucleoporin forming a luminal ring around the NPC, may serve as a potential structural stabiliser. With the support of the Marie Skłodowska-Curie Actions programme, the ProtectNPC project will investigate how Nup210 maintains NPC integrity and prevents NE rupture under stress. Using cryo-electron tomography, researchers will study how Nup210 responds to mechanical strain. The findings will deepen understanding of NPC resilience and shed light on cancer-associated cellular mechanisms.
Objective
The nuclear envelope (NE) is a double-membrane structure that encloses and protects the genetic material in eukaryotes. It is intermitted by nuclear pore complexes (NPCs), which form channels across the NE and mediate nucleocytoplasmic exchange. High tension in the NE is known to invoke NPC dilation, involving structural changes of the NPC scaffold. It is unknown to date, which NPC constituents limit maximum dilation to prevent NPC disintegration under high NE tension, and if disintegration of NPCs can result in NE rupture and nucleocytoplasmic mixing. A putative candidate for protecting NPC structure under mechanical strain is the nucleoporin 210 (Nup210). It is upregulated in several cancers, emerging as a biomarker for breast cancer metastasis and important for cellular adhesion and migration. Nup210 mainly resides in the lumen of the NPC-associated NE und forms a luminal ring (LR), which surrounds the entire residual NPC. In the proposed project, I will assess the role of the Nup210 LR in maintaining NPC structure to prevent disintegration and potential NE rupture under mechanical strain. For this, I will apply focused ion beam milling, cryo electron tomography and advanced image processing techniques to control and Nup210 depleted human cells under differing conditions of NE tension. The comparison of NPC structures will reveal how the Nup210 LR contributes to NPC structural integrity on a molecular level. I will further resolve the conformational landscape of the Nup210 LR to determine whether it elastically accommodates NPC dilation and re-constriction. These structural studies will be complemented and functionally validated by analysing nucleocytoplasmic exchange and NE rupture in the presence and absence of Nup210 in cells. The insights into NPC scaffold integrity and the contribution of the Nup210 LR, and the workflows developed in this project will be of great interest to the structural biology, NPC, NE and mechanobiology research communities.
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.
This project's classification has been human-validated.
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.
This project's classification has been human-validated.
Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
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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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
MAIN PROGRAMME
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Topic(s)
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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.
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) HORIZON-MSCA-2024-PF-01
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80539 MUNCHEN
Germany
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