Assembly of eIF3 Mediated by Mutually Dependent Subunit Insertion

Eukaryotic initiation factor 3 (eIF3), an essential multi-protein complex involved in translation initiation, is composed of 12 tightly associated subunits in humans. While the overall structure of eIF3 is known, the mechanism of its assembly and structural consequences of dysregulation of eIF3 subunit expression seen in many cancers is largely unknown. Here we show that subunits in eIF3 assemble into eIF3 in an interdependent manner. Assembly of eIF3 is governed primarily by formation of a helical bundle, composed of helices extending C-terminally from PCI-MPN domains in eight subunits. We propose that, while the minimal subcomplex of human-like eIF3 functional for translation initiation in cells consists of subunits a, b, c, f, g, i, and m, numerous other eIF3 subcomplexes exist under circumstances of subunit over- or underexpression. Thus, eIF3 subcomplexes formed or “released” due to dysregulated subunit expression may be determining factors contributing to eIF3-related cancers. [Display omitted] •The assembly of many subunits into eIF3 is interdependent•Assembly of eIF3 is ordered and depends on C-terminal helices in PCI-MPN subunits•Dysregulated eIF3 assembly could play important roles in cancer and disease Dysregulation of eIF3 subunit expression has been linked to various cancers. Smith et al. propose an ordered assembly pathway of eIF3 in which subunit dysregulation could form or liberate eIF3 subcomplexes that modulate cellular processes and contribute to cancer.