The Nuclear Pore Complex: Birth, Life, and Death of a Cellular Behemoth

Abstract

Nuclear pore complexes (NPCs) are the only transport channels that cross the nuclear envelope. Constructed from ~500–1000 nucleoporin proteins each, they are among the largest macromolecular assemblies in eukaryotic cells. Thanks to advances in structural analysis approaches, the construction principles and architecture of the NPC have recently been revealed at submolecular resolution. Although the overall structure and inventory of nucleoporins are conserved, NPCs exhibit significant compositional and functional plasticity even within single cells and surprising variability in their assembly pathways. Once assembled, NPCs remain seemingly unexchangeable in post-mitotic cells. There are a number of as yet unresolved questions about how the versatility of NPC assembly and composition is established, how cells monitor the functional state of NPCs or how they could be renewed. Here, we review current progress in our understanding of the key aspects of NPC architecture and lifecycle.

Nuclear basket protein ZC3HC1 and its yeast homolog Pml39p feature an evolutionary conserved bimodular construction essential for initial binding to NPC-anchored homologs of scaffold protein TPR

“…One of them, already mentioned further above, will have been the poor sequence similarity between Sc Pml39p and Hs ZC3HC1, which prevented finding the other species’ homolog through standard primary sequence alignment searches. The other reason why Pml39p, identified in a synthetic lethal screen with a nup133 Δ mutant (Palancade et al , 2005), appears not to have been generally considered a bona fide NB protein (Köhler & Hurt, 2007, 2010; Grossman et al, 2012; Niepel et al, 2013; Floch et al, 2014; Ptak et al, 2014; Obado et al, 2016; Lin & Hoelz, 2019; Fernandez-Martinez & Rout, 2021; Dultz et al, 2022) might be similar to the reason which for long prevented detecting Hs ZC3HC1 as an NB protein: While ZC3HC1 is a protein stably bound to the NB under physiological conditions, it is rapidly detached when exposed to the non-physiological conditions of standard cell fractionation protocols (Gunkel et al , 2021; Gunkel & Cordes, 2022). Furthermore, once the genuine in vivo interactions between native TPR and ZC3HC1 polypeptides have been disrupted in such a way, notable amounts of these parted proteins do not appear inclined to readily re-associate again in vitro , even when having re-instated conditions that more closely again resemble those within cells.…”

Y-complex nucleoporins independently contribute to nuclear pore assembly and gene regulation in neuronal progenitors

“…As channels embedded in the nuclear envelope, the nuclear pore complexes (NPCs) constitute the only gateway for selective transport of macromolecules between the cytoplasm and the nucleus. These impressive structures are composed of proteins called nucleoporins (Nups) that assemble in a highly organized and modular manner (reviewed in Dultz et al, (2022)). The Y-complex - also named Nup107-160 complex - that comprises in vertebrates nine distinct proteins, is a key structural subunit of the NPC scaffold.…”

An ESCRT grommet cooperates with a diffusion barrier to maintain nuclear integrity

“…Nucleocytoplasmic compartmentalization relies on the integrity of these membranes and the selective barrier properties of nuclear pore complexes (NPCs) embedded in the NE (Dultz et al, 2022). During mitosis, the NE barrier presents a challenge for the spindle as it must access the duplicated chromosomes to faithfully segregate the genome to each daughter cell.…”

“…The NE is contiguous with the endoplasmic reticulum (ER) but is functionally specialized due to a unique proteome that populates its constituent inner, outer, and nuclear pore membranes. Nucleocytoplasmic compartmentalization relies on the integrity of these membranes and the selective barrier properties of nuclear pore complexes (NPCs) embedded in the NE (Dultz et al, 2022). During mitosis, the NE barrier presents a challenge for the spindle as it must access the duplicated chromosomes to faithfully segregate the genome to each daughter cell.…”