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Abstract:
Nuclear pore complexes (NPCs) mediate nucleocytoplasmic transport. Their intricate 120-megadalton architecture remains incompletely understood. Here, we report a 70-megadalton model of the human
NPC scaffold with explicit membrane and in multiple conformational states. We combined artificial intelligence (AI)–based structure prediction with in situ and in cellulo cryo–electron tomography and integrative modeling. We show that linker nucleoporins spatially organize the scaffold within and across subcomplexes to establish the higher-order structure. Microsecond-long molecular dynamics simulations
suggest that the scaffold is not required to stabilize the inner and outer nuclear membrane fusion but rather widens the central pore. Our work exemplifies how AI-based modeling can be integrated with
in situ structural biology to understand subcellular architecture across spatial organization levels.
