Structure and Function of the Nuclear Pore Complex

Overview

Journal Cold Spring Harb Perspect Biol

Specialties Biology
Molecular Biology

Date 2022 Sep 12

PMID 36096637

Authors

Stefan Petrovic

George W Mobbs

Christopher J Bley

Si Nie

Alina Patke

Andre Hoelz

Affiliations

Soon will be listed here.

Abstract

The nucleus, a genome-containing organelle eponymous of eukaryotes, is enclosed by a double membrane continuous with the endoplasmic reticulum. The nuclear pore complex (NPC) is an ∼110-MDa, ∼1000-protein channel that selectively transports macromolecules across the nuclear envelope and thus plays a central role in the regulated flow of genetic information from transcription to translation. Its size, complexity, and flexibility have hindered determination of atomistic structures of intact NPCs. Recent studies have overcome these hurdles by combining biochemical reconstitution and docking of high-resolution structures of NPC subcomplexes into cryo-electron tomographic reconstructions with biochemical and physiological validation. Here, we provide an overview of the near-atomic composite structure of the human NPC, a milestone toward unlocking a molecular understanding of mRNA export, NPC-associated diseases, and viral host-pathogen interactions, serving as a paradigm for studying similarly large complexes.

Citing Articles

Strategies for the Viral Exploitation of Nuclear Pore Transport Pathways.

Zhang X, Lim K, Qiu Y, Hazawa M, Wong R Viruses. 2025; 17(2).

PMID: 40006906 PMC: 11860923. DOI: 10.3390/v17020151.

Mechanisms of PP2A-Ankle2 dependent nuclear reassembly after mitosis.

Li J, Wang X, Jordana L, Bonneil E, Ginestet V, Ahmed M Elife. 2025; 13.

PMID: 39964262 PMC: 11835388. DOI: 10.7554/eLife.104233.

Structural basis for a nucleoporin exportin complex between RanBP2, SUMO1-RanGAP1, the E2 Ubc9, Crm1 and the Ran GTPase.

Baytshtok V, DiMattia M, Lima C bioRxiv. 2025; .

PMID: 39763778 PMC: 11703149. DOI: 10.1101/2024.10.04.616749.

Imaging-based quantitative assessment of biomolecular condensates in vitro and in cells.

Bergsma T, Steen A, Kamenz J, Otto T, Otto T, Gallardo P J Biol Chem. 2024; 301(2):108130.

PMID: 39725032 PMC: 11803855. DOI: 10.1016/j.jbc.2024.108130.

The pro-oncogenic noncanonical activity of a RAS•GTP:RanGAP1 complex facilitates nuclear protein export.

Tripathi B, Hirsh N, Qian X, Durkin M, Wang D, Papageorge A Nat Cancer. 2024; 5(12):1902-1918.

PMID: 39528835 PMC: 11663792. DOI: 10.1038/s43018-024-00847-5.

References

Zhang X, Chen S, Yoo S, Chakrabarti S, Zhang T, Ke T . Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death. Cell. 2008; 135(6):1017-27. DOI: 10.1016/j.cell.2008.10.022. View

Reid S, Valmas C, Martinez O, Sanchez F, Basler C . Ebola virus VP24 proteins inhibit the interaction of NPI-1 subfamily karyopherin alpha proteins with activated STAT1. J Virol. 2007; 81(24):13469-77. PMC: 2168840. DOI: 10.1128/JVI.01097-07. View

Huang G, Zhan X, Zeng C, Liang K, Zhu X, Zhao Y . Cryo-EM structure of the inner ring from the Xenopus laevis nuclear pore complex. Cell Res. 2022; 32(5):451-460. PMC: 9061766. DOI: 10.1038/s41422-022-00633-x. View

Reichelt R, Holzenburg A, Buhle Jr E, Jarnik M, Engel A, Aebi U . Correlation between structure and mass distribution of the nuclear pore complex and of distinct pore complex components. J Cell Biol. 1990; 110(4):883-94. PMC: 2116066. DOI: 10.1083/jcb.110.4.883. View

Mishra A, Sipma W, Veenhoff L, Van der Giessen E, Onck P . The Effect of FG-Nup Phosphorylation on NPC Selectivity: A One-Bead-Per-Amino-Acid Molecular Dynamics Study. Int J Mol Sci. 2019; 20(3). PMC: 6387328. DOI: 10.3390/ijms20030596. View

Rapoport T, Jungnickel B, Kutay U . Protein transport across the eukaryotic endoplasmic reticulum and bacterial inner membranes. Annu Rev Biochem. 1996; 65:271-303. DOI: 10.1146/annurev.bi.65.070196.001415. View

Whittle J, Schwartz T . Architectural nucleoporins Nup157/170 and Nup133 are structurally related and descend from a second ancestral element. J Biol Chem. 2009; 284(41):28442-28452. PMC: 2788893. DOI: 10.1074/jbc.M109.023580. View

Funasaka T, Nakano H, Wu Y, Hashizume C, Gu L, Nakamura T . RNA export factor RAE1 contributes to NUP98-HOXA9-mediated leukemogenesis. Cell Cycle. 2011; 10(9):1456-67. DOI: 10.4161/cc.10.9.15494. View

Faria P, Chakraborty P, Levay A, Barber G, Ezelle H, Enninga J . VSV disrupts the Rae1/mrnp41 mRNA nuclear export pathway. Mol Cell. 2005; 17(1):93-102. DOI: 10.1016/j.molcel.2004.11.023. View

10.

Petrovic S, Samanta D, Perriches T, Bley C, Thierbach K, Brown B . Architecture of the linker-scaffold in the nuclear pore. Science. 2022; 376(6598):eabm9798. PMC: 9867570. DOI: 10.1126/science.abm9798. View

11.

Kobayashi W, Takizawa Y, Aihara M, Negishi L, Ishii H, Kurumizaka H . Structural and biochemical analyses of the nuclear pore complex component ELYS identify residues responsible for nucleosome binding. Commun Biol. 2019; 2:163. PMC: 6499780. DOI: 10.1038/s42003-019-0385-7. View

12.

Ori A, Banterle N, Iskar M, Andres-Pons A, Escher C, Khanh Bui H . Cell type-specific nuclear pores: a case in point for context-dependent stoichiometry of molecular machines. Mol Syst Biol. 2013; 9:648. PMC: 3619942. DOI: 10.1038/msb.2013.4. View

13.

Allegretti M, Zimmerli C, Rantos V, Wilfling F, Ronchi P, Fung H . In-cell architecture of the nuclear pore and snapshots of its turnover. Nature. 2020; 586(7831):796-800. DOI: 10.1038/s41586-020-2670-5. View

14.

Pal K, Bandyopadhyay A, Zhou X, Xu Q, Marciano D, Brunzelle J . Structural Basis of TPR-Mediated Oligomerization and Activation of Oncogenic Fusion Kinases. Structure. 2017; 25(6):867-877.e3. PMC: 5507626. DOI: 10.1016/j.str.2017.04.015. View

15.

Matreyek K, Yucel S, Li X, Engelman A . Nucleoporin NUP153 phenylalanine-glycine motifs engage a common binding pocket within the HIV-1 capsid protein to mediate lentiviral infectivity. PLoS Pathog. 2013; 9(10):e1003693. PMC: 3795039. DOI: 10.1371/journal.ppat.1003693. View

16.

Kohler A, Hurt E . Exporting RNA from the nucleus to the cytoplasm. Nat Rev Mol Cell Biol. 2007; 8(10):761-73. DOI: 10.1038/nrm2255. View

17.

Partridge J, Schwartz T . Crystallographic and biochemical analysis of the Ran-binding zinc finger domain. J Mol Biol. 2009; 391(2):375-89. PMC: 2716403. DOI: 10.1016/j.jmb.2009.06.011. View

18.

Gould V, Martinez N, Orucevic A, Schneider J, Alonso A . A novel, nuclear pore-associated, widely distributed molecule overexpressed in oncogenesis and development. Am J Pathol. 2000; 157(5):1605-13. PMC: 1885726. DOI: 10.1016/S0002-9440(10)64798-0. View

19.

Debler E, Ma Y, Seo H, Hsia K, Noriega T, Blobel G . A fence-like coat for the nuclear pore membrane. Mol Cell. 2008; 32(6):815-26. DOI: 10.1016/j.molcel.2008.12.001. View

20.

von Appen A, Kosinski J, Sparks L, Ori A, DiGuilio A, Vollmer B . In situ structural analysis of the human nuclear pore complex. Nature. 2015; 526(7571):140-143. PMC: 4886846. DOI: 10.1038/nature15381. View