A “spindle and thread” mechanism unblocks p53 translation by modulating N-terminal disorder

• Main Authors: Abelein, A. (Author), Arsenian-Henriksson, M. (Author), Chen, G. (Author), Fritz, N. (Author), Ghadessy, F.J (Author), Ilag, L.L (Author), Johansson, J. (Author), Kaldmäe, M. (Author), Koeck, P.J.B (Author), Kronqvist, N. (Author), Lama, D. (Author), Landreh, M. (Author), Lane, D.P (Author), Ng, A.S (Author), Nilsson, L. (Author), Österlund, N. (Author), Rising, A. (Author), Sabatier, P. (Author), Sahin, C. (Author), Saluri, M. (Author), Sarr, M. (Author), Sedimbi, S. (Author), Siau, J.W (Author), Väänänen, V.A (Author), Vojtesek, B. (Author), Vosselman, T. (Author), Zhong, X. (Author), Zubarev, R.A (Author)
• Format: Article
• Language: English
• Published: Cell Press 2022
• Subjects: intrinsically disordered proteins; protein folding; protein translation; tumor suppressor
• Online Access: View Fulltext in Publisher
• ISBN: 09692126 (ISSN)
• DOI: 10.1016/j.str.2022.02.013

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. © 2022 The Author(s)