Kaldmäe M, Vosselman T, Zhong X, Lama D, Chen G, Saluri M, Kronqvist N, Siau JW, Ng AS, Ghadessy FJ, Sabatier P, Vojtesek B, Sarr M, Sahin C, Österlund N, Ilag LL, Väänänen VA, Sedimbi S, Arsenian-Henriksson M, Zubarev RA, Nilsson L, Koeck PJB, Rising A, Abelein A, Fritz N, Johansson J, Lane DP, Landreh M
Structure - (-) - [2022-03-10; online 2022-03-10]
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.