8AS5

CryoEM structure of the human Nucleophosmin 1 core

Summary for 8AS5

• Entry DOI: 10.2210/pdb8as5/pdb
• EMDB information: 15606
• Descriptor: Nucleophosmin (1 entity in total)
• Functional Keywords: phase separation, chaperone
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 5
• Total formula weight: 163540.70

Authors

Valentin Gese, G.,Hallberg, B.M. (deposition date: 2022-08-18, release date: 2023-02-15, Last modification date: 2024-07-24)

Primary citation

Saluri, M.,Leppert, A.,Gese, G.V.,Sahin, C.,Lama, D.,Kaldmae, M.,Chen, G.,Elofsson, A.,Allison, T.M.,Arsenian-Henriksson, M.,Johansson, J.,Lane, D.P.,Hallberg, B.M.,Landreh, M.
A "grappling hook" interaction connects self-assembly and chaperone activity of Nucleophosmin 1.
Pnas Nexus, 2:pgac303-pgac303, 2023

PubMed Abstract: 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.

PubMed: 36743470
DOI: 10.1093/pnasnexus/pgac303

Experimental method

ELECTRON MICROSCOPY (3.53 Å)