Christopher J Bley, Si Nie, George W Mobbs, Stefan Petrovic, Anna T Gres, Xiaoyu Liu, Somnath Mukherjee, Sho Harvey, Ferdinand M Huber, Daniel H Lin, Bonnie Brown, Aaron W Tang, Emily J Rundlet, Ana R Correia, Shane Chen, Saroj G Regmi, Taylor A Stevens, Claudia A Jette, Mary Dasso, Alina Patke, Alexander F Palazzo, Anthony A Kossiakoff, André Hoelz
Science. 2022 Jun 10;376(6598):eabm9129. doi: 10.1126/science.abm9129. Epub 2022 Jun 1
The nuclear pore complex (NPC) is the sole bidirectional gateway for nucleocytoplasmic transport. Despite recent progress in elucidating the NPC symmetric core architecture, the asymmetrically decorated cytoplasmic face, essential for messenger RNA (mRNA) export and a hotspot for nucleoporin-associated diseases, has remained elusive. Here we report a composite structure of the human cytoplasmic face obtained by combining biochemical reconstitution, crystal structure determination, docking into cryo–electron tomographic reconstructions, and physiological validation. Whereas species-specific motifs anchor an evolutionarily conserved ~540-kilodalton heterohexameric cytoplasmic filament nucleoporin complex above the central transport channel, attachment of the NUP358 pentameric bundles depends on the double-ring arrangement of the coat nucleoporin complex. Our composite structure and its predictive power provide a rich foundation for elucidating the molecular basis of mRNA export and nucleoporin diseases.