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How the self-assembly of partially disordered proteins generates functional compartments in the cytoplasm and particularly in the nucleus is poorly understood. Nucleophosmin 1 (NPM1) is an abundant nucleolar protein that forms large oligomers which provide the scaffold for ribosome assembly but also prevent protein aggregation as part of the cellular stress response. Examining the relationship between the self-assembly and chaperone activity of NPM1, we find that oligomerization of full-length NPM1 modulates its ability to retard amyloid formation in vitro. Machine learning and cryo-electron microscopy reveal fuzzy interactions between the disordered region and the C-terminal nucleotide-binding domain that cross-link NPM1 pentamers into oligomers. Ribosomal peptides mediate in a tighter association within the oligomers, reducing their capacity to prevent amyloid formation. We conclude that NPM1 uses a “grappling hook” interaction to form a network-like structure whose chaperone activity is tuned by basic proteins, suggesting a regulatory mechanism for the nucleolar stress response.

Protein disorder is a major hurdle for structural biology. A prominent example is the tumour suppressor p53, whose low expression levels and poor conformational stability due to a high degree of disorder pose major challenges to the development of cancer therapeutics. Here, we address these issues by fusing p53 to an engineered spider silk domain termed NT*. The chimeric protein displays highly efficient translation in vitro and in E. coli and is fully active in human cancer cells. The transmission electron microscopy structure and native mass spectrometry reveal that the full-length p53 fusion protein adopts a compact conformation. Molecular dynamics simulations show that the disordered transactivation domain of p53 is wound around the NT* domain via a series of folding events, resulting in a globular structure. We find that expression of B-Raf, another partially disordered cancer target, is similarly enhanced by fusion to NT*. In summary, we demonstrate how inducing co-translational folding via a molecular “spindle and thread” mechanism can overcome poor translation efficiency of partially disordered proteins.