Molecular architecture of the inner ring scaffold of the human nuclear pore complex

Abstract

Nuclear pore complexes (NPCs) are 110-megadalton assemblies that mediate nucleocytoplasmic transport. NPCs are built from multiple copies of ~30 different nucleoporins, and understanding how these nucleoporins assemble into the NPC scaffold imposes a formidable challenge. Recently, it has been shown how the Y complex, a prominent NPC module, forms the outer rings of the nuclear pore. However, the organization of the inner ring has remained unknown until now. We used molecular modeling combined with cross-linking mass spectrometry and cryo-electron tomography to obtain a composite structure of the inner ring. This architectural map explains the vast majority of the electron density of the scaffold. We conclude that despite obvious differences in morphology and composition, the higher-order structure of the inner and outer rings is unexpectedly similar.

Integrative structure and functional anatomy of a nuclear pore complex

“…Generally, the inner ring appears most conserved 37,38 , as seen in a comparison of our yeast structure with the human scaffold 6 , although the latter is more expanded (Extended Data Fig. 10).…”

“…3A–B,D–E). Though largely absent from recent EM maps 6 , a membrane protein ring interconnects adjacent spokes within the NE lumen (Fig. 3A,E).…”

“…Our structure suggests how each of these challenges are met and, by comparison with the vertebrate scaffold 6 , how different organisms may meet these challenges (below).…”

“…Recently, certain disordered connectors have been shown to be important for holding parts of the scaffold together 6,7,16 . However, the full extent to which such connectors are critical to NPC integrity can only be appreciated in light of the present structure.…”

“…It has also been suggested that the central channel contains a feature called the central transporter 5 . Although partial structures have been described 3,6,7 , a full, high-resolution structure for the entire NPC in any organism has 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-nanometer precision.…”