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[[Image:NTCP_mech.png|left|600 px|thumb| '''Figure 5: Diagram of Proposed Bile Salt Transport Process''']]
[[Image:NTCP_mech.png|left|600 px|thumb| '''Figure 5: Diagram of Proposed Bile Salt Transport Process''']]
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A proposed pathway for NTCP bile salt transport suggests that both sodium ions are translocated with the transport of one bile salt.<Ref name = "Liu"> Liu, H., Irobalieva, R.N., Bang-Sørensen, R. et al. Structure of human NTCP reveals the basis of recognition and sodium-driven transport of bile salts into the liver. Cell Res 32, 773–776 (2022). https://doi.org/10.1038/s41422-022-00680-4 </Ref> In this mechanism both sodium ions are released along with the inner bile salt into the cytoplasm (Fig. 5). The outermost bile salt remains bound however in the pore, likely helping to prevent leakage. <Ref name = "Liu"> The movement of sodium ions then facilitates the conformational change to the inward-facing, pore inaccessible conformation that is believed to displace the outer bile salt into the inner bile salt placement (Fig. 5). </Ref name = "Liu"> Sodium ion then bind to NTCP, favoring the open-pore state and also allowing for the binding of another outer bile salt (Fig 5). The process can then start again releasing the next inner bile salt with the translocation of the sodium ions into the cytoplasm.
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A proposed pathway for NTCP bile salt transport suggests that both sodium ions are translocated with the transport of one bile salt.<Ref name = "Liu"> Liu, H., Irobalieva, R.N., Bang-Sørensen, R. et al. Structure of human NTCP reveals the basis of recognition and sodium-driven transport of bile salts into the liver. Cell Res 32, 773–776 (2022). https://doi.org/10.1038/s41422-022-00680-4 </Ref> Initally all <scene name='95/952721/Mech_step_1/1'>ligands and sodium ions are bound</scene> then both sodium ions are released along with the inner bile salt into the cytoplasm (Fig. 5). The <scene name='95/952721/Mech_step_2/2'>outermost bile salt remains bound</scene> however in the pore, likely helping to prevent leakage. <Ref name = "Liu"/> The <scene name='95/952721/Mech_step_3/2'> outer bile salt is displaced </scene> into the inner bile salt placement by the movement of sodium ions that facilitates the conformational change to the inward-facing, pore inaccessible conformation (Fig. 5). <Ref name = "Liu"/> It utilizes an [https://www.sciencedirect.com/science/article/pii/S0092867417302891 elevator-alternating mechanism] where one domain <font color='#6060ff'><b>(core)</b></font> does most of the translocation, and the other domain <font color='red'><b>(panel)</b></font> remains stationary. <Ref name = "Asami"> Asami, J., Kimura, K.T., Fujita-Fujiharu, Y. et al. Structure of the bile acid transporter and HBV receptor NTCP. Nature 606, 1021–1026 (2022). https://doi.org/10.1038/s41586-022-04845-4 </ref> Sodium ions then bind to NTCP, favoring the open-pore state and also allowing for the binding of another outer bile salt (Fig 5). The <scene name='95/952721/Mech_step_1/1'>protein is then reset</scene> and the process can then start again releasing the next inner bile salt with the translocation of the sodium ions into the cytoplasm.
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== HBV Binding and Infection==
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NTCP is the only [https://rupress.org/jcb/article/195/7/1071/54877/The-cell-biology-of-receptor-mediated-virus entry receptor] into the liver for HBV. <Ref name = "Asami"/> The [https://en.wikipedia.org/wiki/Myristoylation myristolated] PreS1 domain of HBV binds to NTCP through a <scene name='95/952721/Hbv_patch/2'>hydrophobic patch</scene> containing <b><font color='#00e080'><b>residues 157-165</b></font> on the open pore surface. <Ref name = "Asami"/> These residues form part of the tunnel resulting in HBV binding and bile salt transport directly competing and interfering with one another. <Ref name = "Asami"/> Another hydrophobic patch consisting of <b><font color='#00e080'><b>residues 84-87</b></font> found on the N-terminus of NTCP does not overlap with bile salt binding and may be used for the development of [https://en.wikipedia.org/wiki/Antiviral_drug antivirals] that don't inhibit bile uptake <Ref name = "Park"/>. Other minor variations within NTCP provide species specificity for HBV or virus resistance, such as mutant S267F found in East Asia. <Ref name = "Park"/>
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The exact mechanism by which NTCP mediates viral internalization is still yet to be determined; however, current studies speculate it works through [https://en.wikipedia.org/wiki/Viral_entry#Entry_via_endocytosis endocytosis.] <Ref name = "Herrscher"> Herrscher C, Roingeard P, Blanchard E. Hepatitis B Virus Entry into Cells. Cells. 2020 Jun 18;9(6):1486. doi: 10.3390/cells9061486. PMID: 32570893; PMCID: PMC7349259. </ref> Once HBV is bound the NTCP/HBV complex is taken into the cell where viral contents are dumped into the cytoplasm to then begin [https://en.wikipedia.org/wiki/Viral_replication viral replication]. It is currently unknown whether HBV also interacts with other receptors or host cell factors, but NTCP alone is not sufficient for infection. <Ref name = "Herrscher"/>
== Medical Relevancy ==
== Medical Relevancy ==

Revision as of 00:28, 7 April 2023

Sodium Taurocholate Co-Transporting Polypeptide

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References

  1. Stieger B. The role of the sodium-taurocholate cotransporting polypeptide (NTCP) and of the bile salt export pump (BSEP) in physiology and pathophysiology of bile formation. Handb Exp Pharmacol. 2011;(201):205-59. doi: 10.1007/978-3-642-14541-4_5. PMID: 21103971. DOI: DOI: 10.1007/978-3-642-14541-4_5.
  2. Geyer, J., Wilke, T. & Petzinger, E. The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships. Naunyn Schmied Arch Pharmacol 372, 413–431 (2006). https://doi.org/10.1007/s00210-006-0043-8
  3. 3.0 3.1 3.2 Park, JH., Iwamoto, M., Yun, JH. et al. Structural insights into the HBV receptor and bile acid transporter NTCP. Nature 606, 1027–1031 (2022). https://doi.org/10.1038/s41586-022-04857-0.
  4. 4.0 4.1 Goutam, K., Ielasi, F.S., Pardon, E. et al. Structural basis of sodium-dependent bile salt uptake into the liver. Nature 606, 1015–1020 (2022). DOI: 10.1038/s41586-022-04723-z.
  5. Qi X. and Li W. (2022). Unlocking the secrets to human NTCP structure. The Innovation 3(5), 100294. https://doi.org/10.1016/j.xinn.2022.100294
  6. 6.0 6.1 6.2 Liu, H., Irobalieva, R.N., Bang-Sørensen, R. et al. Structure of human NTCP reveals the basis of recognition and sodium-driven transport of bile salts into the liver. Cell Res 32, 773–776 (2022). https://doi.org/10.1038/s41422-022-00680-4
  7. 7.0 7.1 7.2 7.3 Asami, J., Kimura, K.T., Fujita-Fujiharu, Y. et al. Structure of the bile acid transporter and HBV receptor NTCP. Nature 606, 1021–1026 (2022). https://doi.org/10.1038/s41586-022-04845-4
  8. 8.0 8.1 Herrscher C, Roingeard P, Blanchard E. Hepatitis B Virus Entry into Cells. Cells. 2020 Jun 18;9(6):1486. doi: 10.3390/cells9061486. PMID: 32570893; PMCID: PMC7349259.

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