Integrative structure and functional anatomy of a nuclear pore complex

Seung Joong Kim, Javier Fernandez-Martinez, Ilona Nudelman, Yi Shi, Wenzhu Zhang, Barak Raveh, Thurston Herricks, Brian D. Slaughter, Joanna A. Hogan, Paula Upla, Ilan E. Chemmama, Riccardo Pellarin (+20 others)
2018 Nature  
0 0 M o n t h 2 0 1 8 | V o L 0 0 0 | n A t U R E | 1 ARticLE Nuclear pore complexes (NPCs) are large proteinaceous assemblies studded through the nuclear envelope, the double-membraned barrier that surrounds the nucleus; NPCs are the sole mediators of macromolecular transport between the nucleus and the cytoplasm, and carry key regulatory platforms for numerous nuclear processes 1 . NPCs are also major targets for viral manipulation and defects in this transport machine are directly linked to
more » ... uman diseases, including cancers 2 . Each NPC is an eight-fold symmetric, cylindrical assembly consisting of approximately 550 copies of about 30 different proteins of the nucleoporin family (Nups). These Nups assemble into sub-complexes that form higher-order structures called spokes. Eight spokes assemble into even larger modules: coaxial outer and inner rings form a symmetric core scaffold, which is connected to a membrane ring, a nuclear basket and cytoplasmic RNA export complexes 3 . The scaffold surrounds a central channel that is formed in part by multiple intrinsically disordered Phe-Gly (FG) repeat motifs that extend from nucleoporins termed FG Nups. These FG motifs mediate selective nucleocytoplasmic transport through specific interactions with nuclear transport factors (NTFs), which carry their cognate macromolecular cargoes 4 . It has also previously been suggested that the central channel contains a feature called the central transporter 5 . Although partial structures have previously been described 3,6,7 , a complete, high-resolution structure for the entire NPC in any organism has hitherto been lacking, leaving open key questions as to how the NPC is organized and functions, and how it evolved. To address these questions, we have determined an integrative structure of the yeast NPC at sub-nanometre precision. Nuclear pore complexes play central roles as gatekeepers of RNA and protein transport between the cytoplasm and nucleoplasm. However, their large size and dynamic nature have impeded a full structural and functional elucidation. Here we determined the structure of the entire 552-protein nuclear pore complex of the yeast Saccharomyces cerevisiae at sub-nanometre precision by satisfying a wide range of data relating to the molecular arrangement of its constituents. The nuclear pore complex incorporates sturdy diagonal columns and connector cables attached to these columns, imbuing the structure with strength and flexibility. These cables also tie together all other elements of the nuclear pore complex, including membrane-interacting regions, outer rings and RNA-processing platforms. Inwardly directed anchors create a high density of transport factor-docking Phe-Gly repeats in the central channel, organized into distinct functional units. This integrative structure enables us to rationalize the architecture, transport mechanism and evolutionary origins of the nuclear pore complex.
doi:10.1038/nature26003 pmid:29539637 fatcat:y5o267xpkfhk3e4fagdjuycjzm