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Introduction
Sodium-taurocholate Co-transporting Polypeptide (NTCP) is found within the membrane of hepatocyte, and its primary role is to facilitate the transport of bile salts into hepatocytes from the bloodstream. This is important because 90% of human bile salts are recycled daily, so the function of NTCP is critical in providing bile salts to solubilize fats for digestion. Bile salts are derived from cholesterol, and they serve an important role in the mechanical digestion of fats and ultimately facilitate the chemical digestion of lipids. Their mixture of hydrophobic and hydrophilic regions allow them to act as a bridge between aqueous and lipid environments. In the small intestine, bile salts emulsify fats and cholesterol into micelles. Without bile, fats would spontaneously separate out of the aqueous mixture in the duodenum and would not be accessible to pancreatic lipase to break down fat in your diet. Proper fat digestion requires both pancreatic lipase and bile, so the working transport of bile salts through NTCP in necessary to facilitate this action. In addition to transporting bile salts into the cytoplasm of hepatocytes, NTCP also serves as a receptor for Hepatitis B (HBV) and Hepatitis D (HDV) viruses.
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Function
Bile Salt Uptake
HBV/HDV Infection
Structure
Structures were determined by cryogenic electron microscopy (Cryo-EM) of NTCP in complex with antibodies or nanobodies that stabilize both of these conformations. There are nine transmembrane alpha helices traversing the plasma membrane with the N-terminus located on the extracellular side of the plasma membrane and the C-terminus located on the intracellular side. The panel domain is formed by transmembrane helices TM1, TM5, and TM6. The core domain is formed by the packing of a helix bundle consisting of TM2, TM3, and TM4 with another helix bundle consisting of TM7, TM8, and TM9. The two helix bundles are related by pseudo two-fold symmetry. Transmembrane helices are connected by short loops as well as extracellular and intracellular alpha helices that lie nearly parallel to the membrane.
Proline/Glycine Hinge
Core & Panel Domains
Sodium Binding Sites
To transport a single bile salt from the blood to the cytoplasm of the liver cell, two sodium ions are required to be bound to to NTCP in the open-pore state in association with specific residues of the molecule. This is because the transport of bile salts into the cell is so thermodynamically unfavorable , the reaction has to be coupled to the favorable transport of 2 sodium into into the cell. When the bile salts are released into the cell, the protein is then reverted to the inward facing conformation, in which the pore through which the bile salt had just passed is now closed. This is an example of secondary active transport. The residues interacting with the sodium ion in sodium binding site #1 includes S105, N106, E257, and T123. The residues interacting with the sodium ion in sodium binding site #2 includes Q261 and Q68. Mutations to these significant residues will inhibit the binding of sodium ions, and therefore, inhibit the overall function of NTCP.
Sodium Binding Sites
Significant Residues
Molecular Mechanism
Mechanism of Bile Salt Uptake
Mechanism of HBV/HDV Infection
Medical Relevance
Relevance
This is a sample scene created with SAT to color by Group, and another to make a transparent representation of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.
- ↑ Asami J, Kimura KT, Fujita-Fujiharu Y, Ishida H, Zhang Z, Nomura Y, Liu K, Uemura T, Sato Y, Ono M, Yamamoto M, Noda T, Shigematsu H, Drew D, Iwata S, Shimizu T, Nomura N, Ohto U. Structure of the bile acid transporter and HBV receptor NTCP. Nature. 2022 Jun; 606 (7916):1021-1026. DOI: 10.1038/s41586-022-04845-4.
- ↑ Goutam K, Ielasi FS, Pardon E, Steyaert J, Reyes N. Structural basis of sodium-dependent bile salt uptake into the liver. Nature. 2022 Jun;606(7916):1015-1020. DOI: 10.1038/s41586-022-04723-z.
- ↑ Park JH, Iwamoto M, Yun JH, Uchikubo-Kamo T, Son D, Jin Z, Yoshida H, Ohki M, Ishimoto N, Mizutani K, Oshima M, Muramatsu M, Wakita T, Shirouzu M, Liu K, Uemura T, Nomura N, Iwata S, Watashi K, Tame JRH, Nishizawa T, Lee W, Park SY. Structural insights into the HBV receptor and bile acid transporter NTCP. Nature. 2022 Jun;606(7916):1027-1031. DOI: 10.1038/s41586-022-04857-0.
- ↑ Liu H, Irobalieva RN, Bang-Sørensen R, Nosol K, Mukherjee S, Agrawal P, Stieger B, Kossiakoff AA, Locher KP. Structure of human NTCP reveals the basis of recognition and sodium-driven transport of bile salts into the liver. Cell Res. 2022 Aug;32(8):773-776. DOI: 10.1038/s41422-022-00680-4.
- ↑ Qi X, Li W. Unlocking the secrets to human NTCP structure. Innovation (Camb). 2022 Aug 1;3(5):100294. doi: 10.1016/j.xinn.2022.100294. DOI: 10.1016/j.xinn.2022.100294.
- ↑ Zhang X, Zhang Q, Peng Q, Zhou J, Liao L, Sun X, Zhang L, Gong T. Hepatitis B virus preS1-derived lipopeptide functionalized liposomes for targeting of hepatic cells. Biomaterials. 2014 Jul;35(23):6130-41. doi: 10.1016/j.biomaterials.2014.04.037. DOI: 10.1016/j.biomaterials.2014.04.037.
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