A “grappling hook” interaction connects self-assembly and chaperone activity of Nucleophosmin 1

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 and undergoes liquid-liquid phase separation by binding RNA or ribosomal proteins. It provides the scaffold for ribosome assembly but also prevents protein aggregation as part of the cellular stress response. Here, we use aggregation assays and native mass spectrometry (MS) to examine 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-based structure prediction and cryo-electron microscopy reveal fuzzy interactions between the acidic disordered region and the C-terminal nucleotide-binding domain, which cross-link NPM1 pentamers into partially disordered oligomers. The addition of basic peptides results in a tighter association within the oligomers, reducing their capacity to prevent amyloid formation. Together, our findings show that NPM1 uses a grappling hook mechanism to form a network-like structure that traps aggregation-prone proteins. Nucleolar proteins and RNAs simultaneously modulate the association strength and chaperone activity, suggesting a mechanism by which nucleolar composition regulates the chaperone activity of NPM1.

Leppert, AxelKarolinska Institutet (author)
Gese, Genis ValentinKarolinska Institutet (author)
Sahin, CaglaKarolinska Institutet (author)
Lama, DilrajKarolinska Institutet (author)
Kaldmae, Margit (author)
Chen, GefeiKarolinska Institutet (author)
Elofsson, Arne,1966-Stockholms universitet,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab)(Swepub:su)aelof (author)
Allison, Timothy M. (author)
Arsenian-Henriksson, MarieKarolinska Institutet (author)
Johansson, JanKarolinska Institutet (author)
Lane, David P. (author)
Hallberg, B. MartinKarolinska Institutet (author)
Landreh, MichaelKarolinska Institutet (author)
Karolinska InstitutetInstitutionen för biokemi och biofysik (creator_code:org_t)

By the author/editor: Saluri, Mihkel; Leppert, Axel; Gese, Genis Vale ...; Sahin, Cagla; Lama, Dilraj; Kaldmae, Margit; show more...; Chen, Gefei; Elofsson, Arne, ...; Allison, Timothy ...; Arsenian-Henriks ...; Johansson, Jan; Lane, David P.; Hallberg, B. Mar ...; Landreh, Michael; show less...

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

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