Project description
The impact of mutations in protein assembly
Understanding how mutations disrupt protein structure and function is central for comprehending diseases. The working hypothesis of the EU-funded Agglomerates project is that mutations can have another impact; they can change a protein’s surface chemistry and alter its supramolecular self-assembly, leading to the generation of large polymeric structures. Researchers will study this phenomenon, known as protein agglomeration, using yeast as a model system. They will also predict polymorphisms that trigger agglomeration and further investigate the potential of translating this effect in drug design. Project results will provide important insight into the implication of agglomeration in cell physiology.
Objective
Understanding how proteins respond to mutations is of paramount importance to biology and disease. While protein stability and misfolding have been instrumental in rationalizing the impact of mutations, we recently discovered that an alternative route is also frequent, where mutations at the surface of symmetric proteins trigger novel self-interactions that lead to infinite self-assembly. This mechanism can be involved in disease, as in sickle-cell anemia, but may also serve in adaptation. Importantly, it differs fundamentally from aggregation, because misfolding does not drive it. Thus, we term it “agglomeration”. The ease with which agglomeration can occur, even by single point mutations, shifts the paradigm of how quickly new protein assemblies can emerge, both in health and disease. This prompts us to determine the basic principles of protein agglomeration and explore its implications in cell physiology and human disease.
We propose an interdisciplinary research program bridging atomic and cellular scales to explore agglomeration in three aims: (i) Map the landscape of protein agglomeration in response to mutation in endogenous yeast proteins; (ii) Characterize how yeast physiology impacts agglomeration by changes in gene expression or cell state, and, conversely, how protein agglomerates impact yeast fitness. (iii) Analyze agglomeration in relation to human disease via two approaches. First, by predicting single nucleotide polymorphisms that trigger agglomeration, prioritizing them using knowledge from Aims 1 & 2, and characterizing them experimentally. Second, by providing a proof-of-concept that agglomeration can be exploited in drug design, whereby drugs induce its formation, like mutations can do.
Overall, through this research, we aim to establish agglomeration as a paradigm for protein assembly, with implications for our understanding of evolution, physiology, and disease.
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Funding Scheme
ERC-COG - Consolidator GrantHost institution
1211 Geneve
Switzerland