XPO5

Description

The XPO5 (exportin 5) is a protein-coding gene located on chromosome 6.

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 (also known as pre-miRNA) out of the nucleus and into the cytoplasm, for further processing by the Dicer enzyme. 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. 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.

== Mechanism ==

=== Binding to pre-miRNA ===

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.

=== 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.

XPO5, also known as Exportin-5 or Ran-binding protein 21, facilitates the movement of molecules out of the nucleus. It specifically binds to double-stranded RNA (dsRNA) and proteins containing a dsRNA binding domain (dsRBD), forming a complex with RanGTP (an active form of the GTPase Ran). This complex then interacts with nucleoporins, proteins that make up the nuclear pore complex (NPC), allowing it to move through the pore. Once in the cytoplasm, RanGTP is hydrolyzed to RanGDP, causing the complex to disassemble and release the dsRNA or dsRBD-containing protein. XPO5 then returns to the nucleus to repeat the process. This export process is directed by the higher concentration of RanGTP in the nucleus and RanGDP in the cytoplasm. Overexpression of XPO5 can increase the effectiveness of RNA interference (RNAi), a mechanism that uses RNA to silence genes.

XPO5 is also known as exp5.

Associated Diseases

WES Whole Exome Sequencing