Project description
Mechanistic insight into prion formation
Prions are proteins that can transform into a self-propagating and infectious aggregated state causing disease such as the transmissible spongiform encephalopathies. In the yeast, a particular protein behaves like a prion and offers a survival advantage to the host by prolonging proliferation upon nutrient exhaustion. The EU-funded DEEPCONSTRUCT project is interested to understand the role of intrinsically disordered regions (IDRs) in prion formation and activity. IDRs lack secondary or tertiary structure and challenge previous conceptions that biological function is linked to 3D structure. Researchers will follow a mutagenesis approach to decipher sequence-function relationships of IDRs in yeast. Given that IDRs are implicated in diseases such as Alzheimer’s and Parkinson’s, results will have important clinical projections.
Objective
Intrinsically disordered regions (IDRs) are pervasive in eukaryotic proteomes despite their poor evolutionary conservation. IDRs have recently gained considerable interest as drivers of the formation of biomolecular condensates, representing a novel fundamental principle of eukaryotic subcellular organization. However, a detailed mechanistic description of how intra and intermolecular interactions drive the formation, stability and physical properties of condensates is lacking.
In this project, we will apply deep mutagenesis scans (DMS) to gain insight into sequence-function relationships of IDRs using the remarkable yeast [SMAUG+] non-amyloid prion as a model system. [SMAUG+] is induced through transient overexpression of the RNA binding protein Vts1, leading to the formation of gel-like condensates that are epigenetically inherited through cell divisions. In addition, [SMAUG+] condensates can act as protein-based infectious agents that transform naïve cells. We propose to massively mutagenize Vts1 IDRs and measure the individual and combinatorial effects of IDR mutations on [SMAUG+] formation and stability. This will allow us to gain insight into the mechanisms of condensate formation and prionogenic activity of [SMAUG+], and potentially uncover the structures of condensed [SMAUG+] through analysis of the genetic interactions (epistasis) between mutations. Finally, we will use automated microscopy of selected mutants to understand how mutations affect the inheritance of the prion.
The insights obtained from this DMS analysis will be combined with information from previous genome-wide prion formation assays in order to build predictive models of non-amyloid prionogenic activity from protein sequence. The ultimate goal is to translate these models into metazoan proteomes, including human, in order to define novel non-amyloid prion candidates and begin to characterize their functions in non-genetic protein-based inheritance in normal development and in disease.
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 physical sciences optics microscopy
- natural sciences biological sciences genetics mutation
- natural sciences biological sciences genetics RNA
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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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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 - Marie Skłodowska-Curie Individual Fellowships (IF)
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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-2020
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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.
08003 Barcelona
Spain
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