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PreprintCited by 1RNA Research and SplicingProtein Structure and DynamicsRNA and protein synthesis mechanisms

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Human Pumilio proteins use fuzzy multivalent hydrophobic interactions to recruit the CCR4–NOT deadenylase complex to repress mRNAs

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Dunshee, Elise B., Saladin, Brenna A., Turner, David J., Qiu, Chen, Dutcher, Robert C., Williams, Jason G., Corbo, Joshua, Wolcott, Olivia R., Korte, Amanda J., Haugen, Rebecca J., Tanaka Hall, Traci M., Valkov, Eugene, Goldstrohm, Aaron C.·2025·Journal of Biological Chemistry
DOI 10.64898/2025.12.18.695197PMC PMC12993204

Preprint — published as 10.1016/j.jbc.2026.111281 · Paper page

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Abstract

Pumilio (PUM) proteins are conserved RNA-binding proteins that control mRNAs involved in development, proliferation, and stem cell differentiation. Human PUM1 and PUM2 repress targets by recruiting the CCR4–NOT deadenylase complex through a metazoan-specific N-terminal repression domain (RD3), which is predicted to be intrinsically disordered. Here we dissect RD3 using cell-based reporter assays, protein interaction assays with recombinant proteins, and crosslinking mass spectrometry. We identify multiple short RD3 peptides that are sufficient for repression and bind directly to the C-terminal NOT module of CCR4–NOT, comprising CNOT1, CNOT2, and CNOT3 subunits. Crosslinking reveals numerous mutually exclusive contacts between RD3 and the NOT module, consistent with a multivalent “fuzzy” binding mode in which interactions are not defined by a single sequence or structure. Sequence scrambling shows that the linear amino acid order of RD3 is dispensable, whereas its physicochemical composition, in particular distributed aliphatic and aromatic residues, is essential for repression and CCR4–NOT binding. These findings support a model in which low-affinity, multivalent interactions between intrinsically disordered regions (IDRs) and effector complexes, governed by amino acid composition rather than precise sequence, underlie robust PUM-mediated repression, and exemplify general principles by which IDRs recruit the CCR4–NOT complex to regulate gene expression. Graphical Abstract:

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Metadata

Authors
Dunshee, E. B., Saladin, B. A., Turner, D. J., Qiu, C., Dutcher, R. C., Williams, J. G., Corbo, J., Wolcott, O. R., Korte, A. J., Haugen, R. J., Tanaka Hall, T. M., Valkov, E., & Goldstrohm, A. C.
Affiliations
  • University of Minnesota (US)
  • National Institutes of Health (US)
Corresponding author
Goldstrohm, Aaron C.
ORCID
Venue
Journal of Biological Chemistry
Publisher
openRxiv
Published
2025-12-20
Volume
302
Issue
4
Pages
111281-111281
ISSN
0021-9258 (ISSN-L)
DOI
10.64898/2025.12.18.695197
PMC
PMC12993204
OpenAlex
W7128687749
Cited by
1
References
1
Citations by year
2026: 1
FWCI
2.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Institute of General Medical Sciences (R01 GM150468)
  • National Institute of Environmental Health Sciences (ZIA-ES050165, ZIC ES103005)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords
Pumilio proteins, PUM1, PUM2, mRNA deadenylation, mRNA repression, intrinsically disordered regions, multivalent interactions, hydrophobic interactions, amino acid composition, RNA-binding proteins, gene expression regulation

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