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The nuclear pore complex: understanding its function through structural insight

Nature Reviews Molecular Cell Biology volume 18, pages 73–89 (2017)Cite this article

Subjects

Key Points

  • Structural, biochemical and cell biology investigations of the nuclear pore complex (NPC) over the past 60 years have contributed to explaining its canonical features.

  • Recently, in vitro and in situ investigations have converged to produce the first pseudo-atomic model of the NPC central core.

  • It seems that nucleoporins, the building blocks of the NPC, are conformationally labile and locally adapt to serve multiple structural roles.

  • A network of short linear motifs is essential for holding the scaffold of the NPC together and offers a novel and attractive scientific concept of how scaffolding might be regulated by post-translational modifications.

  • Prospectively, these structural insights might trigger novel types of investigations that will shed light on the mechanism behind nucleocytoplasmic transport (as well as other functions of the NPC) and the disease-relevance of nucleoporin dysfunction.

Abstract

Nuclear pore complexes (NPCs) fuse the inner and outer nuclear membranes to form channels across the nuclear envelope. They are large macromolecular assemblies with a complex composition and diverse functions. Apart from facilitating nucleocytoplasmic transport, NPCs are involved in chromatin organization, the regulation of gene expression and DNA repair. Understanding the molecular mechanisms underlying these functions has been hampered by a lack of structural knowledge about the NPC. The recent convergence of crystallographic and biochemical in vitro analysis of nucleoporins (NUPs), the components of the NPC, with cryo-electron microscopic imaging of the entire NPC in situ has provided first pseudo-atomic view of its central core and revealed that an unexpected network of short linear motifs is an important spatial organization principle. These breakthroughs have transformed the way we understand NPC structure, and they provide an important base for functional investigations, including the elucidation of the molecular mechanisms underlying clinically manifested mutations of the nucleocytoplasmic transport system.

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Figure 1: Molecular architecture, composition and functions of nuclear pores.
Figure 2: Timeline of hallmark discoveries in structural NPC research.
Figure 3: Short linear motifs in NUPs connect major NPC modules.
Figure 4: Architecture and organization of the NPC scaffold.
Figure 5: Mutations in human NUPs may affect NPC structure and function to lead to disease.

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Acknowledgements

The authors are grateful to A. Neal for his constructive comments on the manuscript. M.B. acknowledges funding from the European Molecular Biology Laboratory and the European Research Council (309271-NPCAtlas). E.H. is a recipient of a grant from the Deutsche Forschungsgemeinschaft (DFG Hu363/10-1). The authors apologize to those authors whose publications could not be cited owing to space limitations.

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Authors and Affiliations

  1. European Molecular Biology Laboratory, Structural and Computational Biology Unit, Meyerhofstrasse 1, Heidelberg, D-69117, Germany

    Martin Beck

  2. Biochemistry Center of Heidelberg University, INF328, Heidelberg, D-69120, Germany

    Ed Hurt

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Supplementary information

Supplementary information S1 (table)

List of Chaetomium thermophilum, yeast and metazoan nucleoporins. (PDF 130 kb)

Supplementary information S2 (box)

Overproduced Nups sequester factors crucial for cell proliferation away from the NPC (PDF 101 kb)

PowerPoint slides

Glossary

Transcriptional memory

Genes expressed in proximity to nuclear pore complexes (gene gating) might remain there after their inactivation in order to be more rapidly re-activated.

Pseudo-atomic resolution

When atomic resolution has not been obtained directly but by a secondary method — such as by fitting multiple atomically resolved X-ray structures into a lower resolved cryo-electron microscopy structure — so not all aspects of the resulting structural model can be considered atomically resolved.

Nuclear lamina

A fibrillar intermediate filament network associated with the inner nuclear membrane. It consists of lamins, which can be categorized into A-type (lamins A and C) and B-type (lamins B1 and B2).

Composite epitope

An epitope present in various nucleoporins (NUPs), which turned out to be Phe- and Gly-repeats (FG-repeats), a low complexity sequence that is crucial to the function of FG-repeat-containing NUPs (FG-NUPs).

O-Linked β-N-acetylglucosamine modification

(O-GlcNAc modification). A post-translational modification that is attached to many FG-repeat-containing nucleoporins (FG-NUPs) by the enzyme O-GlcNAc transferase.

Epitope tagging

A technique in which a known epitope (for example, encoding an affinity tag) is fused to a bait protein, making it possible to detect and affinity-purify proteins for which no antibody is available.

Immuno-electron microscopy

An electron microscopy technique in which colloidal gold particle-conjugated antibodies are used to visualize the position of proteins or epitope-tagged proteins.

Pseudosymmetric

Strictly speaking, nuclear pore complexes are only eightfold rotationally symmetric with respect to the nucleocytoplasmic (central channel) axis. As a different subset of nucleoporins binds to the cytoplasmic and nuclear rings, the arrangement with respect to the nuclear envelope plane is often referred to as pseudosymmetric.

Particle averaging

Computational image processing to combine the information from many complexes (particles) into a single structure.

Non-isotropically resolved

Visualized in a manner that gives an incomplete or distorted view. Because nuclear pore complexes were primarily imaged in top view, the resulting structures were distorted along the nucleocytoplasmic axis; for example, the inner and outer nuclear membranes were not resolved.

Cryo-electron tomography

An imaging technique in which the object of interest is rotated within the cryo-electron microscope during the imaging and a virtual volume (tomogram) is subsequently calculated from the images.

Hydrogel

A network of polymer chains (in this case, FG-repeat-containing nucleoporins (FG-NUPs) in which water is the dispersion medium.

Ancestral coatomer elements

(ACEs). A type of α-helical repeat domain found in several scaffold nucleoporins that is similar to HEAT (huntingtin, elongation factor 3, protein phosphatase 2A and TOR1) repeats but has a distinct arrangement of helices. As ACEs are also found in SEC31 of the coat protein complex II (COPII) coat, it has been argued that vesicle coats and nuclear pores are evolutionarily related.

Amphipathic motifs

Motifs found in many proteins that contain both polar and apolar properties. Amphipathic motifs can be responsible for associating proteins with membranes.

Asymmetric unit

One of the eight rotational segments of the nuclear pore. It has also been referred to as a protomer, the smallest unit of a protein complex, which forms larger hetero-oligomers by associating multiple copies of this unit with each other.

Epigenetic chromatin modification

Covalent post-translational histone modification by methylation, phosphorylation, acetylation, ubiquitylation or sumoylation, which can influence gene expression by altering chromatin structure or recruiting histone modifiers.

Aneuploidy

The presence of an abnormal number of chromosomes in a cell.

Glomerular podocytes

Cells in the Bowman's capsule of the kidney that wrap around the capillaries of the glomerulus and filter urine.

Meiotic DNA-damage response

A checkpoint control that monitors meiotic recombination during meiosis, blocking the entry into metaphase I as long as recombination is not efficiently established.

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Beck, M., Hurt, E. The nuclear pore complex: understanding its function through structural insight. Nat Rev Mol Cell Biol 18, 73–89 (2017). https://doi.org/10.1038/nrm.2016.147

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