The Nuclear Pore Complex Has Entered the Atomic Age

Abstract

Nuclear pore complexes (NPCs) perforate the nuclear envelope and represent the exclusive passageway into and out of the nucleus of the eukaryotic cell. Apart from their essential transport function, components of the NPC have important, direct roles in nuclear organization and in gene regulation. Due to its central role in cell biology, it is of considerable interest to determine the NPC structure at atomic resolution. The complexity of these large, 40-60 MDa protein assemblies has for decades limited such structural studies. More recently, exploiting the intrinsic modularity of the NPC, structural biologists are making progress toward understanding this nanomachine in molecular detail. Structures of building blocks of the stable, architectural scaffold of the NPC have been solved, and distinct models for their assembly proposed. Here we review the status of the field and lay out the challenges and the next steps toward a full understanding of the NPC at atomic resolution.

Structural Characterization of Bardet-Biedl Syndrome 9 Protein (BBS9)

“…The protein acts in the context of the octameric BBSome, which forms a membrane coat to select membrane-inserted cargo destined for the primary cilium. The cell has several such membrane coating systems, like COPI, COPII, clathrin and, more distantly related, the nuclear pore complex (36). The architecture of these assemblies is principally related, presumably because of a common evolutionary past (37,38).…”

Membrane-coating lattice scaffolds in the nuclear pore and vesicle coats

“…4 In an effort to extend the repertoire of nup structures and to form a better understanding of the overall architecture of the NPC, we solved the structure of the Nup85•Seh1 heterodimer, one of the two short arms of the Y-complex. 10 The structure shows that Seh1 forms an open six-bladed β-propeller that is completed in trans by a three-stranded insertion blade at EXTRA VIEW EXTRA VIEW ACE1 domains form the symmetrical edge elements of the lattice, while four Sec31-β-propellers from adjacent edges form the vertex elements in the assembled COPII coat.…”

“…Biochemical and structural studies have characterized the interactions between nucleoporins within the Y-complex. 4 Interactions between the stacked helical domains of the components Nup133, Nup84, Nup145C, Nup120 and Nup85 appear sufficient to assemble its branched Y-shaped structure. The β-propeller domains, of which there are four (N-terminal domains of Nup133 and Nup120, Seh1 and Sec13), are not central to these interactions, leaving them as candidates for mediating interactions outside of the Y.…”

“…Architecturally, the NPC is composed of ∼30 nucleoporins (nups) which assemble into a set of subcomplexes that are repeated around a central axis with eight-fold rotational symmetry. 3 The heptameric Nup84 and the heteromeric Nic96 complexes form the stable structural scaffold, 4 which anchors the phenylalanine glycine (FG) repeat nups responsible for translocation of transport receptor-cargo complexes across the NE. The 575 kDa Nup84 complex is composed of Nup145C, Nup133, Nup120, Nup85, Nup84, Sec13 and Seh1 in S. cerevisiae, while in metazoa additional members have been reported.…”

Molecular basis for Nup37 and ELY5/ELYS recruitment to the nuclear pore complex

“…The pores are lined with massive protein assemblies, called nuclear pore complexes (NPCs) (2,3). Principally conserved in all eukaryotes, NPCs are estimated to be ∼50 MDa in size and composed of ∼30 different proteins (nucleoporins or Nups), which are arranged in multiple copies around a central eightfold rotational axis (4). Apart from the well-known transport function (5)(6)(7), NPCs participate in a number of additional cellular processes, including nuclear organization, cell cycle regulation, chromatin maintenance, and DNA repair (8).…”