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 The arrangement of NPCs in the nuclear envelope. (A) In a vertebrate NPC, nucleoporins are arranged 
with striking eightfold rotational symmetry. In addition, immunoelectron microscope studies show that the proteins that make 
up the central portion of the NPC are oriented symmetrically across the nuclear envelope, so that the nuclear and cytosolic 
sides look identical. The eightfold rotational and twofold transverse symmetry explains how such a huge structure can be 
formed from only about 30 different proteins: many of the nucleoporins are present in 8, 16, or 32 copies. On the basis of 
their approximate localization in the central portion of the NPC, nucleoporins can be classified into (1) transmembrane ring 
proteins that span the nuclear envelope and anchor the NPC to the envelope; (2) scaffold nucleoporins that form layered 
ring structures (some scaffold nucleoporins are membrane-bending proteins that stabilize the sharp membrane curvature 
where the nuclear envelope is penetrated); and (3) channel nucleoporins that line a central pore. In addition to folded domains 
that anchor the proteins in specific places, many channel nucleoporins contain extensive unstructured regions, where 
the polypeptide chains are intrinsically disordered. The central pore is filled with a high concentration of these disordered 
domains whose weak interactions with each other form a gel that blocks the passive diffusion of large macromolecules. The 
disordered regions contain a large number of phenylalanine–glycine (FG) repeats. Fibrils protrude from both the cytosolic and 
the nuclear sides of the NPC. By contrast to the twofold transverse symmetry of the NPC core, the fibrils facing the cytosol 
and nucleus are different: on the nuclear side, the fibrils converge at their distal end to form a basketlike structure. The precise 
arrangement of individual nucleoporins in the assembled NPC is still a matter of intense debate, because atomic resolution 
analyses have been hindered by the sheer size and flexible nature of the NPC and by difficulties in purifying sufficient 
amounts of homogeneous material. A combination of electron microscopy, computational analyses, and crystal structures of 
nucleoporin subcomplexes has been used to develop the current models of the NPC architecture. (B) A scanning electron 
micrograph of the nuclear side of the nuclear envelope of an oocyte, showing NPCs with their basketlike fibrils. (C) An  
electron micrograph showing a side view of two NPCs (brackets); note that the inner and outer nuclear membranes are 
continuous at the edges of the pore. (D) An electron micrograph showing face-on views of negatively stained NPCs. The 
membrane has been removed by detergent extraction. Note that some of the NPCs contain material in their center, which is 
thought to be trapped macromolecules in transit through these NPCs. (A, adapted from A. Hoelz et al., Annu. Rev. Biochem. 
80:613–643, 2011. B, © 1992 M.W. Goldberg and T.D. Allen. Originally published in J. Cell Biol. https://doi.org/10.1083/
 jcb.119.6.1429. With permission from Rockefeller University Press. C, courtesy of Werner Franke and Ulrich Scheer. D, 
courtesy of Ron Milligan.)