Disordered regions of human eIF4B orchestrate a dynamic self-association landscape

Bikash Chandra Swain, Pascale Sarkis, Vanessa Ung, Sabrina Rousseau, Laurent Fernandez, Ani Meltonyan, V. Esperance Aho, Davide Mercadante, Cameron D. Mackereth () and Mikayel Aznauryan ()
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Bikash Chandra Swain: Institut Européen de Chimie et Biologie
Pascale Sarkis: Institut Européen de Chimie et Biologie
Vanessa Ung: University of Auckland
Sabrina Rousseau: Institut Européen de Chimie et Biologie
Laurent Fernandez: Institut Européen de Chimie et Biologie
Ani Meltonyan: Institut Européen de Chimie et Biologie
V. Esperance Aho: Institut Européen de Chimie et Biologie
Davide Mercadante: University of Auckland
Cameron D. Mackereth: UMR 5320
Mikayel Aznauryan: Institut Européen de Chimie et Biologie

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Eukaryotic translation initiation factor eIF4B is required for efficient cap-dependent translation, it is overexpressed in cancer cells, and may influence stress granule formation. Due to the high degree of intrinsic disorder, eIF4B is rarely observed in cryo-EM structures of translation complexes and only ever by its single structured RNA recognition motif domain, leaving the molecular details of its large intrinsically disordered region (IDR) unknown. By integrating experiments and simulations we demonstrate that eIF4B IDR orchestrates and fine-tunes an intricate transition from monomers to a condensed phase, in which large-size dynamic oligomers form before mesoscopic phase separation. Single-molecule spectroscopy combined with molecular simulations enabled us to characterize the conformational ensembles and underlying intra- and intermolecular dynamics across the oligomerization transition. The observed sensitivity to ionic strength and molecular crowding in the self-association landscape suggests potential regulation of eIF4B nanoscopic and mesoscopic behaviors such as driven by protein modifications, binding partners or changes to the cellular environment.

Date: 2024
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DOI: 10.1038/s41467-024-53136-1

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