Nuclear transport

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Nuclear transport refers to the mechanisms by which molecules move across the nuclear membrane of a cell. The entry and exit of large molecules from the cell nucleus is tightly controlled by the nuclear pore complexes (NPCs). Although small molecules can enter the nucleus without regulation, [1] macromolecules such as RNA and proteins require association with transport factors known as nuclear transport receptors, like karyopherins called importins to enter the nucleus and exportins to exit. [2] [3]

Contents

Nuclear import

Protein that must be imported to the nucleus from the cytoplasm carry nuclear localization signals (NLS) that are bound by importins. An NLS is a sequence of amino acids that acts as a tag. They are most commonly hydrophilic sequences containing lysine and arginine residues, although diverse NLS sequences have been documented. [1] Proteins, transfer RNA, and assembled ribosomal subunits are exported from the nucleus due to association with exportins, which bind signaling sequences called nuclear export signals (NES). The ability of both importins and exportins to transport their cargo is regulated by the Ran small G-protein.

Macromolecules, such as RNA and proteins, are actively transported across the nuclear membrane in a process called the Ran-GTP nuclear transport cycle. Rancycle nuclearimport nuclearexport.png
Macromolecules, such as RNA and proteins, are actively transported across the nuclear membrane in a process called the Ran-GTP nuclear transport cycle.

G-proteins are GTPase enzymes that bind to a molecule called guanosine triphosphate (GTP) which they then hydrolyze to create guanosine diphosphate (GDP) and release energy. The RAN enzymes exist in two nucleotide-bound forms: GDP-bound and GTP-bound. In its GTP-bound state, Ran is capable of binding importins and exportins. Importins release cargo upon binding to RanGTP, while exportins must bind RanGTP to form a ternary complex with their export cargo. The dominant nucleotide binding state of Ran depends on whether it is located in the nucleus (RanGTP) or the cytoplasm (RanGDP).

Nuclear export

Nuclear export roughly reverses the import process; in the nucleus, the exportin binds the cargo and Ran-GTP and diffuses through the pore to the cytoplasm, where the complex dissociates. Ran-GTP binds GAP and hydrolyzes GTP, and the resulting Ran-GDP complex is restored to the nucleus where it exchanges its bound ligand for GTP. Hence, whereas importins depend on RanGTP to dissociate from their cargo, exportins require RanGTP in order to bind to their cargo. [4]

A specialized mRNA exporter protein moves mature mRNA to the cytoplasm after post-transcriptional modification is complete. This translocation process is actively dependent on the Ran protein, although the specific mechanism is not yet well understood. Some particularly commonly transcribed genes are physically located near nuclear pores to facilitate the translocation process. [5]

Export of tRNA is also dependent on the various modifications it undergoes, thus preventing export of improperly functioning tRNA. This quality control mechanism is important due to tRNA's central role in translation, where it is involved in adding amino acids to a growing peptide chain. The tRNA exporter in vertebrates is called exportin-t. Exportin-t binds directly to its tRNA cargo in the nucleus, a process promoted by the presence of RanGTP. Mutations that affect tRNA's structure inhibit its ability to bind to exportin-t, and consequentially, to be exported, providing the cell with another quality control step. [6] As described above, once the complex has crossed the envelope it dissociates and releases the tRNA cargo into the cytosol.

Protein shuttling

Many proteins are known to have both NESs and NLSs and thus shuttle constantly between the nucleus and the cytosol. In certain cases one of these steps (i.e., nuclear import or nuclear export) is regulated, often by post-translational modifications.

Nuclear import limits the propagation of large proteins expressed in skeletal muscle fibers and possibly other syncytial tissues, maintaining localized gene expression in certain nuclei. [7] Combining both NESs and NLSs promotes propagation of large proteins to more distant nuclei in muscle fibers. [8]

Protein shuttling can be assessed using a heterokaryon fusion assay. [9]

Related Research Articles

<span class="mw-page-title-main">Cell nucleus</span> Eukaryotic membrane-bounded organelle containing DNA

The cell nucleus is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have no nuclei, and a few others including osteoclasts have many. The main structures making up the nucleus are the nuclear envelope, a double membrane that encloses the entire organelle and isolates its contents from the cellular cytoplasm; and the nuclear matrix, a network within the nucleus that adds mechanical support.

<span class="mw-page-title-main">Nuclear pore</span> Openings in nuclear envelope of eukaryotic cells

A nuclear pore is a channel as part of the nuclear pore complex (NPC), a large protein complex found in the nuclear envelope in eukaryotic cells, enveloping the cell nucleus containing DNA, which facilitates the selective membrane transport of various molecules across the membrane.

A nuclear localization signalorsequence (NLS) is an amino acid sequence that 'tags' a protein for import into the cell nucleus by nuclear transport. Typically, this signal consists of one or more short sequences of positively charged lysines or arginines exposed on the protein surface. Different nuclear localized proteins may share the same NLS. An NLS has the opposite function of a nuclear export signal (NES), which targets proteins out of the nucleus.

Karyopherins are proteins involved in transporting molecules between the cytoplasm and the nucleus of a eukaryotic cell. The inside of the nucleus is called the karyoplasm. Generally, karyopherin-mediated transport occurs through nuclear pores which act as a gateway into and out of the nucleus. Most proteins require karyopherins to traverse the nuclear pore.

Importin is a type of karyopherin that transports protein molecules from the cell's cytoplasm to the nucleus. It does so by binding to specific recognition sequences, called nuclear localization sequences (NLS).

<span class="mw-page-title-main">Ran (protein)</span> GTPase functioning in nuclear transport

Ran also known as GTP-binding nuclear protein Ran is a protein that in humans is encoded by the RAN gene. Ran is a small 25 kDa protein that is involved in transport into and out of the cell nucleus during interphase and also involved in mitosis. It is a member of the Ras superfamily.

The HIV-1 Rev response element (RRE) is a highly structured, ~350 nucleotide RNA segment present in the Env coding region of unspliced and partially spliced viral mRNAs. In the presence of the HIV-1 accessory protein Rev, HIV-1 mRNAs that contain the RRE can be exported from the nucleus to the cytoplasm for downstream events such as translation and virion packaging.

<span class="mw-page-title-main">Nucleoporin</span> Family of proteins that form the nuclear pore complex

Nucleoporins are a family of proteins which are the constituent building blocks of the nuclear pore complex (NPC). The nuclear pore complex is a massive structure embedded in the nuclear envelope at sites where the inner and outer nuclear membranes fuse, forming a gateway that regulates the flow of macromolecules between the cell nucleus and the cytoplasm. Nuclear pores enable the passive and facilitated transport of molecules across the nuclear envelope. Nucleoporins, a family of around 30 proteins, are the main components of the nuclear pore complex in eukaryotic cells. Nucleoporin 62 is the most abundant member of this family. Nucleoporins are able to transport molecules across the nuclear envelope at a very high rate. A single NPC is able to transport 60,000 protein molecules across the nuclear envelope every minute.

<span class="mw-page-title-main">XPO1</span> Protein-coding gene in the species Homo sapiens

Exportin 1 (XPO1), also known as chromosomal region maintenance 1 (CRM1), is a eukaryotic protein that mediates the nuclear export of various proteins and RNAs.

<span class="mw-page-title-main">KPNB1</span> Protein-coding gene in the species Homo sapiens

Importin subunit beta-1 is a protein that in humans is encoded by the KPNB1 gene.

<span class="mw-page-title-main">IPO5</span> Protein-coding gene in the species Homo sapiens

Importin-5 is a protein that in humans is encoded by the IPO5 gene. The protein encoded by this gene is a member of the importin beta family. Structurally, the protein adopts the shape of a right hand solenoid and is composed of 24 HEAT repeats.

<span class="mw-page-title-main">Nucleoporin 153</span> Protein-coding gene in the species Homo sapiens

Nucleoporin 153 (Nup153) is a protein which in humans is encoded by the NUP153 gene. It is an essential component of the basket of nuclear pore complexes (NPCs) in vertebrates, and required for the anchoring of NPCs. It also acts as the docking site of an importing karyopherin. On the cytoplasmic side of the NPC, Nup358 fulfills an analogous role.

<span class="mw-page-title-main">Transportin 1</span> Protein-coding gene in the species Homo sapiens

Transportin-1 is a protein that in humans is encoded by the TNPO1 gene.

<span class="mw-page-title-main">XPO5</span>

Exportin-5 (XPO5) is a protein that, in humans, is encoded by the XPO5 gene. In eukaryotic cells, the primary purpose of XPO5 is to export pre-microRNA out of the nucleus and into the cytoplasm, for further processing by the Dicer enzyme. Once in the cytoplasm, the microRNA can act as a gene silencer by regulating translation of mRNA. Although XPO5 is primarily involved in the transport of pre-miRNA, it has also been reported to transport tRNA.

<span class="mw-page-title-main">IPO7</span> Protein-coding gene in the species Homo sapiens

Importin-7 is a protein that in humans is encoded by the IPO7 gene.

<span class="mw-page-title-main">XPOT</span> Protein-coding gene in the species Homo sapiens

Exportin-T is a protein that in humans is encoded by the XPOT gene.

<span class="mw-page-title-main">IPO13</span> Protein-coding gene in the species Homo sapiens

Importin-13 is a protein encoded by the IPO13 gene in humans. Importin-13 is a member of the importin-β family of nuclear transport receptors (NTRs) and was first identified as a transport receptor in 2000. According to PSI-blast based secondary structure PREDiction (PSIPRED), importin-13 contains 38 α-helices. Importin-13 accommodates a range of cargoes due to its flexible superhelical structure and a cargo binding and release system that is distinct from other importin-like transport receptors. IPO13 is broadly expressed in a variety of tissues in the human body, including the heart, cornea, fetal lung, brain, endometrial carcinoma, and testes.

A nuclear export signal (NES) is a short target peptide containing 4 hydrophobic residues in a protein that targets it for export from the cell nucleus to the cytoplasm through the nuclear pore complex using nuclear transport. It has the opposite effect of a nuclear localization signal, which targets a protein located in the cytoplasm for import to the nucleus. The NES is recognized and bound by exportins.

<span class="mw-page-title-main">Rev (HIV)</span> HIV-1 regulating protein

Rev is a transactivating protein that is essential to the regulation of HIV-1 protein expression. A nuclear localization signal is encoded in the rev gene, which allows the Rev protein to be localized to the nucleus, where it is involved in the export of unspliced and incompletely spliced mRNAs. In the absence of Rev, mRNAs of the HIV-1 late (structural) genes are retained in the nucleus, preventing their translation.

Importin alpha, or karyopherin alpha refers to a class of adaptor proteins that are involved in the import of proteins into the cell nucleus. They are a sub-family of karyopherin proteins.

References

  1. 1 2 Watson, JD; Baker TA; Bell SP; Gann A; Levine M; Losick R. (2004). "Ch9-10". Molecular Biology of the Gene (5th ed.). Peason Benjamin Cummings; CSHL Press. ISBN   978-0-8053-9603-4.
  2. ↑ Mackmull, MT; Klaus, B; Heinze, I; Chokkalingam, M; Beyer, A; Russell, RB; Ori, A; Beck, M (18 December 2017). "Landscape of nuclear transport receptor cargo specificity". Molecular Systems Biology. 13 (12): 962. doi:10.15252/msb.20177608. PMC   5740495 . PMID   29254951.
  3. ↑ Alberts, Bruce (2004). Essential cell biology (2nd ed.). Garland Science Pub. pp.  504–506. ISBN   978-0815334811.
  4. ↑ Pemberton, Lucy F.; Bryce M. Paschal (2005). "Mechanisms of Receptor-Mediated Nuclear Import and Nuclear Export". Traffic. Blackwell Munksgaard. 6 (3): 187–198. doi: 10.1111/j.1600-0854.2005.00270.x . PMID   15702987. S2CID   172279.
  5. ↑ Cole, CN; Scarcelli, JJ (2006). "Transport of messenger RNA from the nucleus to the cytoplasm". Curr Opin Cell Biol. 18 (3): 299–306. doi:10.1016/j.ceb.2006.04.006. PMID   16682182.
  6. ↑ Görlich, Dirk; Ulrike Kutay (1999). "Transport between the cell nucleus and the cytoplasm". Annu. Rev. Cell Dev. Biol. 15: 607–660. doi:10.1146/annurev.cellbio.15.1.607. PMID   10611974.
  7. ↑ Taylor-Weiner, Hermes; Grigsby, Christopher L.; Ferreira, Duarte M. S.; Dias, José M.; Stevens, Molly M.; Ruas, Jorge L.; Teixeira, Ana I. (2020-02-11). "Modeling the transport of nuclear proteins along single skeletal muscle cells". Proceedings of the National Academy of Sciences of the United States of America. 117 (6): 2978–2986. doi:10.1073/pnas.1919600117. ISSN   0027-8424. PMC   7022209 . PMID   31988126.
  8. ↑ K. K. Poukalov, M. C. Valero, D. R. Muscato, L. M. Adams, H. Chun, Y. il Lee, N. S. Andrade, Z. Zeier, H. L. Sweeney, E. T. Wang, Myospreader improves gene editing in skeletal muscle by myonuclear propagation. bioRxiv [Preprint] (2023). https://doi.org/10.1101/2023.11.06.565807.
  9. ↑ Gammal, Roseann; Baker, Krista; Heilman, Destin (2011). "Heterokaryon Technique for Analysis of Cell Type-specific Localization". Journal of Visualized Experiments (49): 2488. doi:10.3791/2488. ISSN   1940-087X. PMC   3197295 . PMID   21445034.
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