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Research article - Peer-reviewed, 2022

A "spindle and thread"mechanism unblocks p53 translation N-terminal disorder

Kaldmae, Margit; Vosselman, Thibault; Zhong, Xueying; Lama, Dilraj; Chen, Gefei; Saluri, Mihkel; Kronqvist, Nina; Siau, Jia Wei; Ng, Aik Seng; Ghadessy, Farid J.; Sabatier, Pierre; Vojtesek, Borivoj; Sarr, Medoune; Sahin, Cagla; Osterlund, Nicklas; Ilag, Leopold L.; Vaananen, Venla A.; Sedimbi, Saikiran; Arsenian-Henriksson, Marie; Zubarev, Roman A.;
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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.

Published in

2022, Volume: 30, number: 5, pages: 733-742
Publisher: CELL PRESS

    Sustainable Development Goals

    SDG3 Good health and well-being

    UKÄ Subject classification

    Biochemistry and Molecular Biology

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