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

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" bi

SUBMITTER: Dunshee EB 

PROVIDER: S-EPMC12724400 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature