XPO5

Last updated
XPO5
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases XPO5 , exp5, exportin 5
External IDs OMIM: 607845 MGI: 1913789 HomoloGene: 69316 GeneCards: XPO5
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_020750

NM_028198

RefSeq (protein)

NP_065801

NP_082474

Location (UCSC) Chr 6: 43.52 – 43.58 Mb Chr 17: 46.51 – 46.55 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Exportin-5 (XPO5) is a protein that, in humans, is encoded by the XPO5 gene. [5] [6] [7] In eukaryotic cells, the primary purpose of XPO5 is to export pre-microRNA (also known as pre-miRNA) out of the nucleus and into the cytoplasm, for further processing by the Dicer enzyme. [8] [9] [10] [11] Once in the cytoplasm, the microRNA (also known as miRNA) 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. [12]

Contents

Much research on XPO5 is ongoing. miRNA is a prominent research topic due to its potential use as a therapeutic, with several miRNA-based drugs already in use. [13]

Mechanism

Binding to pre-miRNA

Image of XPO5 ternary complex generated in PyMol from crystal structure entry 3A6P in the Protein Data Bank. XPO5 is labeled green, Ran is labeled red, RNA is multi-colored, and GTP is labeled white. XPO5 Image.png
Image of XPO5 ternary complex generated in PyMol from crystal structure entry 3A6P in the Protein Data Bank. XPO5 is labeled green, Ran is labeled red, RNA is multi-colored, and GTP is labeled white.

After RanGTP binds to XPO5, the XPO5-RanGTP complex forms a U-like structure to hold the pre-miRNA. The XPO5-RanGTP complex recognizes pre-miRNA by its two-nucleotide 3’ overhang—a sequence consisting of two bases at the 3’ end of the pre-miRNA that are not paired with other bases. This motif is unique to pre-miRNA, and by recognizing it XPO5 ensures specificity for transporting only pre-miRNA. On its own, pre-miRNA is in a “closed” conformation, with the 3’ overhang flipped up toward the RNA minor groove. However, upon binding to XPO5, the 3’ overhang is flipped downwards away from the rest of the pre-miRNA molecule into an “open” conformation. This helps the backbone phosphates of these two nucleotides form hydrogen bonds with many XPO5 residues, allowing XPO5 to recognize the RNA as pre-miRNA. Because these interactions involve only the RNA phosphate backbone, they are nonspecific and allow XPO5 to recognize and transport any pre-miRNA. The rest of the pre-miRNA stem binds to XPO5 via interactions between the negatively-charged phosphate backbone and several positively-charged interior XPO5 residues. [15]

XPO5 Ternary Complex Transport Mechanism

The combined structure of XPO5, RanGTP, and pre-miRNA is known as the ternary complex. Once the ternary complex is formed, it diffuses through a nuclear pore complex into the cytoplasm, transporting pre-miRNA into the cytoplasm in the process. Once in the cytoplasm, RanGAP hydrolyzes GTP to GDP, causing a conformational change that releases the pre-miRNA into the cytoplasm. [15]

Export out of the Nucleus

It has been suggested, through evidence provided by contour maps of water density, that the interior of XPO5 is hydrophilic, while the exterior of XPO5 is hydrophobic. [15] Therefore, this enhances the binding capabilities of XPO5 to the nuclear pore complex, allowing for transport of the ternary complex out of the nucleus. [15]

Additional interactions

XPO5 has been shown to interact with ILF3 [5] and Ran. [5]

Potential oncogenic role

Recent evidence has shown higher levels of XPO5 in prostate cancer cell lines in-vitro, suggesting that altered XPO5 expression levels may have a role in cancer development. Suppressing XPO5 has also been found to be therapeutic in-vitro. [16] It has also been shown to function as an oncogene in colorectal cancer. [17]

Related Research Articles

<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.

<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.

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, 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.

<span class="mw-page-title-main">Drosha</span> Ribonuclease III enzyme

Drosha is a Class 2 ribonuclease III enzyme that in humans is encoded by the DROSHA gene. It is the primary nuclease that executes the initiation step of miRNA processing in the nucleus. It works closely with DGCR8 and in correlation with Dicer. It has been found significant in clinical knowledge for cancer prognosis and HIV-1 replication.

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">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">RANBP2</span> Protein-coding gene in the species Homo sapiens

RAN binding protein 2 (RANBP2) is protein which in humans is encoded by the RANBP2 gene. It is also known as nucleoporin 358 (Nup358) since it is a member nucleoporin family that makes up the nuclear pore complex. RanBP2 has a mass of 358 kDa.

<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">DDX3X</span> Protein-coding gene in humans

ATP-dependent RNA helicase DDX3X is an enzyme that in humans is encoded by the DDX3X gene.

<span class="mw-page-title-main">RANBP1</span> Protein-coding gene in the species Homo sapiens

Ran-specific binding protein 1 is an enzyme that in humans is encoded by the RANBP1 gene.

<span class="mw-page-title-main">RANBP3</span> Protein-coding gene in the species Homo sapiens

Ran-binding protein 3 is a protein that in humans is encoded by the RANBP3 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">XPO6</span> Protein-coding gene in the species Homo sapiens

Exportin-6 is a protein that in humans is encoded by the XPO6 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.

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

The microprocessor complex is a protein complex involved in the early stages of processing microRNA (miRNA) and RNA interference (RNAi) in animal cells. The complex is minimally composed of the ribonuclease enzyme Drosha and the dimeric RNA-binding protein DGCR8, and cleaves primary miRNA substrates to pre-miRNA in the cell nucleus. Microprocessor is also the smaller of the two multi-protein complexes that contain human Drosha.

References

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  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  16. Höti, Naseruddin; Yang, Shuang; Aiyetan, Paul; Kumar, Binod; Hu, Yingwei; Clark, David; Eroglu, Arife Unal; Shah, Punit; Johnson, Tamara (2017-09-04). "Overexpression of Exportin-5 Overrides the Inhibitory Effect of miRNAs Regulation Control and Stabilize Proteins via Posttranslation Modifications in Prostate Cancer". Neoplasia (New York, N.Y.). 19 (10): 817–829. doi:10.1016/j.neo.2017.07.008. ISSN   1522-8002. PMC   5587889 . PMID   28881308.
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Further reading