The Nuclear Pore Complex as a Flexible and Dynamic Gate

Abstract

Nuclear pore complexes (NPCs) perforate the nuclear envelope and serve as the primary transport gates for molecular exchange between nucleus and cytoplasm. Stripping the megadalton complex down to its most essential organizational elements, one can divide the NPC into scaffold components and the disordered elements attached to them that generate a selective barrier between compartments. These structural elements exhibit flexibility, which may hold a clue in understanding NPC assembly and function. Here we review the current status of NPC research with a focus on the functional implications of its structural and compositional heterogeneity.

Figure 1. Function of the nuclear pore complex in cellular communication

The nuclear pore (NPC) (human proteins, grey, EMDB code 3103, (Appen et al., 2015) coordinates a multitude of transport processes, including nuclear import and export, and viral interactions. Depicted in the cartoon, human hepatitis B virus (cyan, EMDB code 3015) and an import complex comprising importin-β, importin-α, and cargo (blue, green, and yellow, composite of PDB codes 1QGK, 1EE5, 1K5J, respectively) are ready to traverse the NPC. Exiting the nucleus are the 60S pre-ribosomal subunit (yellow-orange, PDB code 1JJ2, and an mRNP comprising the export factor TAP bound to RNA (pink and purple, PDB code 3RW6), and a protein export complex comprising exportin Cse1-Kap60 Cargo-RanGTP (green, PDB code 1WA5).

Figure 2. Overall structure of the NPC

Cryo-electron tomographic (cryo-ET) reconstruction of the human NPC from HeLa cells (EMDB code 3103, (Appen et al., 2015)). Cut-away view showing half of an NPC embedded in the nuclear envelope (yellow). Additional structural elements, i.e., cytoplasmic filaments and nuclear basket that have been excluded from the cryo-ET analysis, are added schematically. Nucleoporins from yeast and metazoa are listed and color-matched according to their approximate positions within the NPC.

Figure 3. Domain architecture of nucleoporins

Yeast nucleoporins with their metazoan homologs are listed. The domain architecture is derived primarily from X-ray crystallographic data, combined with structure prediction whenever experimental data is not yet available. The vast majority of nucleoporins are built from a limited set of structural modules, which characteristically occur in multiple proteins.

Figure 4. Representative large structures and protein complexes from the NPC

(A) Composite structure built from six overlapping individual crystal structures (Kelley et al., 2015). (B) The topology of the trimeric Nsp1-Nup57-Nup49 complex from fungi is identical to the metazoan Nup62-Nup54-Nup58 complex (Chug et al., 2015; Stuwe et al., 2015a). Both complexes are anchored to the NPC scaffold via Nic96/Nup93. Despite low sequence similarity scaffold structures are largely conserved between evolutionarily highly diverged eukaryotic species. (C) Structure of the large scaffold Nup188 built from three segments: bluegreen and blue elements are crystal structures (Andersen et al., 2013) while the grey segment is modeled. All panels are on the same scale.