Editing Nuclear pore complex (section)

== Nuclear transport ==
{{Further|Nuclear transport}}
[[Image:Rancycle nuclearimport nuclearexport.png|thumb|342x342px|The Ran-GTP cycle, which drives the import and export of RNA and proteins through the nuclear protein complex.]]
[[File:3D-SIM-1 NPC Confocal vs 3D-SIM detail.jpg|thumb|349x349px|Scanning and illumination microscopy of nuclear pores, [[nuclear lamina|lamina]], and [[chromatin]].]]

The nuclear pore complex (NPC) serves as a highly regulated gateway for the transport of molecules between the nucleus and the cytoplasm.<ref name="Maimon"/> This intricate system enables the selective passage for molecules including proteins, RNA, and signaling molecules, ensuring proper cellular function and homeostasis. Small molecules such as proteins water and ions can diffuse through NPCs, but cargoes (>40 [[KDa]]) such as RNA and protein require the participation of soluble transport receptors.<ref>{{cite journal |last1=Imamoto |first1=Naoko |last2=Funakoshi |first2=Tomoko |title=Nuclear pore dynamics during the cell cycle |journal=Current Opinion in Cell Biology |date=August 2012 |volume=24 |issue=4 |pages=453–459 |doi=10.1016/j.ceb.2012.06.004 |pmid=22770730 }}</ref>

The largest family of [[Nuclear transport|nuclear transport receptors]] are karyopherins, that include [[importin]]s or [[exportin]]s. These are a superfamily of nuclear transport receptors that facilitate the translocation of proteins, RNAs, and ribonuclear particles across the NPC in a Ran GTP hydrolase-dependent process.<ref>{{cite journal |last1=Mosammaparast |first1=Nima |last2=Pemberton |first2=Lucy F. |title=Karyopherins: from nuclear-transport mediators to nuclear-function regulators |journal=Trends in Cell Biology |date=October 2004 |volume=14 |issue=10 |pages=547–556 |doi=10.1016/j.tcb.2004.09.004 |pmid=15450977 }}</ref> This family is further subdivided to the [[karyopherin]]-α and the [[karyopherin]]-β subfamilies. Other [[Nuclear transport|nuclear transport receptors]] include [[NTF2]] and some NTF2-like proteins.

Three models have been suggested to explain the translocation mechanism:
* Affinity gradients along the central plug
* Brownian affinity gating
* Selective phase

=== Import of proteins ===
{{Main|Nuclear localization signal}}
Nuclear proteins are synthesized in the cytoplasm and need to be imported through the NPCs into the nucleus. Import can be directed by various signals, of which nuclear localization signal (NLS) are best characterized.<ref>{{cite journal |last1=Görlich |first1=Dirk |title=Nuclear protein import |journal=Current Opinion in Cell Biology |date=June 1997 |volume=9 |issue=3 |pages=412–419 |doi=10.1016/s0955-0674(97)80015-4 |pmid=9159081 |hdl=11858/00-001M-0000-002D-1CC5-E |hdl-access=free }}</ref> Several NLS sequences are known, generally containing a conserved sequence with basic residues such as PKKKRKV. Any material with an NLS will be taken up by importins to the nucleus.{{citation needed|date=May 2024}}

Importation begins with Importin-α binding to the NLS sequence of cargo proteins, forming a complex. Importin-β then attaches to Importin-α, facilitating transport towards the NPC.{{citation needed|date=May 2024}}

As the complex reaches the NPC, it diffuses through the pore without the need for additional energy. Upon entry into nucleus, RanGTP binds to Importin-β and displaces it from the complex. Then the ''[[cellular apoptosis susceptibility protein]]'' (CAS), an exportin which in the nucleus is bound to RanGTP, displaces Importin-α from the cargo. The NLS-protein is thus free in the nucleoplasm. The Importinβ-RanGTP and Importinα-CAS-RanGTP complex diffuses back to the cytoplasm where [[Guanosine triphosphate|GTPs]] are hydrolyzed to GDP leading to the release of Importinβ and Importinα which become available for a new NLS-protein import round.{{citation needed|date=May 2024}}

While translocation through the NPC is not energy-dependent, the overall import cycle needs the hydrolysis of two GTPs molecules, making it an active transport process. The import cycle is powered by the nucleo-cytoplasmic RanGTP gradient. This gradient arises from the exclusive nuclear localization of RanGEFs, proteins that exchange GDP to GTP on Ran molecules. Thus, there is an elevated RanGTP concentration in the nucleus compared to the cytoplasm.{{citation needed|date=May 2024}}

=== Export of proteins ===

In addition to nuclear import, certain molecules and macromolecular complexes, such as [[ribosome]] subunits and [[messenger RNA]]s, require export from the nucleus to the cytoplasm. This export process mirrors the import mechanism in complexity and importance.{{citation needed|date=May 2024}}

In a classical export scenario, proteins with a nuclear export sequence (NES) form a [[heterotrimeric]] complex with an exportin and RanGTP within the nucleus. Example of such an exportin is CRM1. This complex subsequently translocate to the [[cytoplasm]], where GTP hydrolysis occurs, releasing the NES-containing protein. The resulting CRM1-RanGDP complex returns to the nucleus, where RanGEFs catalyze the exchange of GDP for GTP on Ran, replenishing the system's energy source. This entire process is energy-dependent and consumes one GTP molecule. Notably, the export activity mediated by CRM1 can be inhibited by compounds like [[leptomycin B]].

=== Export of RNA ===
{{see also|Gene gating}}
Different export pathways through the NPC for various RNA classes. [[RNA]] export is signal-mediated, with nuclear export signals (NES) present in RNA-binding proteins, except for tRNA which lacks an adapter. It is notable that all viral RNAs and cellular RNAs ([[tRNA]], [[rRNA]], [[SnRNA|U snRNA]], [[microRNA]]) except mRNA are dependent on RanGTP. Conserved mRNA export factors are necessary for mRNA nuclear export. Export factors are Mex67/Tap (large subunit) and Mtr2/p15 (small subunit).{{citation needed|date=May 2024}}

In highest eukaryotes, mRNA export is believed to be spicling-dependent. Splicing recruits the TREX protein complex to spliced messages, serving as an adapter for TAP, a low-affinity RNA-binding protein However, there are alternative mRNA export pathways that do not rely on splicing for specialized messages such as histones. Recent work also suggest an interplay between splicing-dependent export and one of these alternative mRNA export pathways for secretory and mitochondrial transcripts.<ref>{{cite journal | vauthors = Cenik C, Chua HN, Zhang H, Tarnawsky SP, Akef A, Derti A, Tasan M, Moore MJ, Palazzo AF, Roth FP | title = Genome analysis reveals interplay between 5'UTR introns and nuclear mRNA export for secretory and mitochondrial genes | journal = PLOS Genetics | volume = 7 | issue = 4 | pages = e1001366 | date = April 2011 | pmid = 21533221 | pmc = 3077370 | doi = 10.1371/journal.pgen.1001366 | doi-access = free }}</ref>