Horizons in Molecular Biology 2017: Architecture of the human nuclear pore - solving a 3D jigsaw with 1000 pieces

Nuclear pore complexes (NPCs) are fundamental components of all eukaryotic cells. They mediate nucleocytoplasmic exchange, regulate gene expression and are of high human health relevance. Elucidating their 110 MDa structure imposes a formidable challenge and requires in situ structural biology approaches. Fifteen out of about thirty nucleoporins (Nups) are structured and form the Y- and inner ring complexes. These two major scaffolding modules assemble in multiple copies into an eight-fold symmetric structure that fuses the inner and outer nuclear membranes to form a central channel of ~60 nm in diameter. The scaffold is decorated with transport channel Nups that often contain phenylalanine (FG)-repeat sequences and mediate the interaction with cargo complexes. Until very recently, it was unclear how the Y- and inner ring complexes oligomerizes in situ. We combined cryo-electron tomography with mass spectrometry, biochemical analysis, perturbation experiments and structural modeling to investigate nuclear pore architecture in situ. We obtained the most comprehensive architectural model of the NPC to date. We conclude that, similarly to coated vesicles­, multiple copies of the same structural building block - although compositionally identical - engage in different local sets of interactions and conformations.


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