Journal
STRUCTURE
Volume 30, Issue 5, Pages 733-+Publisher
CELL PRESS
DOI: 10.1016/j.str.2022.02.013
Keywords
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Funding
- Swedish Foundation for Strategic Research
- Swedish Cancer Society [19 0480]
- Swedish Research Council
- KI-Cancer Blue Sky Grant
- European Regional Development Fund - Project ENOCH [CZ.02.1.01/0.0/0.0/16_ 019/0000868]
- Ministry of Health, Czech Republic -DRO [00209805]
- DoRa plus program - European Regional Development Fund
- Republic of Estonia
- Center for Innovative Medicine at KI (CIMED)
- Vinnova
- Olle Engqvist Foundation
- Swedish Society for Medical Research, FORMAS
- Ake Wiberg Foundation
- Ministry of Science and Higher Education of the Russian Federation [075-15-2020-899]
- Swedish NMR Center at the University of Gothenburg
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Disordered proteins pose challenges to structural biology. Researchers have found that fusing the protein with a highly soluble spider silk domain can modulate its characteristics and enhance translation efficiency. This mechanism is of great significance for cancer treatment.
Disordered proteins pose a major challenge to structural biology. A prominent example is the tumor suppressor p53, whose low expression levels and poor conformational stability hamper the development of cancer therapeutics. All these characteristics make it a prime example of ``life on the edge of solubility.'' Here, we investigate whether these features can be modulated by fusing the protein to a highly soluble spider silk domain (NT*). The chimeric protein displays highly efficient translation and is fully active in human cancer cells. Biophysical characterization reveals a compact conformation, with the disordered transactivation domain of p53 wrapped around the NT* domain. We conclude that interactions with NT* help to unblock translation of the proline-rich disordered region of p53. Expression of partially disordered cancer targets is similarly enhanced by NT*. In summary, we demonstrate that inducing co-translational folding via a molecular ``spindle and thread'' mechanism unblocks protein translation in vitro.
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