Sandbox Reserved 1783

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This Sandbox is Reserved from February 27 through August 31, 2023 for use in the course CH462 Biochemistry II taught by R. Jeremy Johnson at the Butler University, Indianapolis, USA. This reservation includes Sandbox Reserved 1765 through Sandbox Reserved 1795.

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Sodium Taurocholate Co-Transporting Peptide

1 Background
2 Structural Overview
3 Significance
- 3.1 Bile Salt Uptake

Background

Figure 1. NTCP structure with both Na+ ions and bile salts bound with the NTCP molecule shown in light blue, the two Na+ ions shown in purple spheres, and the bile salts shown in sticks as dark blue. [PDB file 7ZYI].

Sodium taurocholate co-transporting polypeptide (NTCP) is a sodium-dependent transporter that is responsible for the transportation of bile salts from the blood into epithelial liver cells. ^[1] NTCP is a secondary active transport molecule that couples the thermodynamically favorable movement of Na+ ions with the unfavorable transport of bile salts into the cell (Fig. 1).

The bile salts transported by NTCP in the gastrointestinal tract are involved in digestion, nutrient absorption, fat breakdown, and lipid soluble nutrient transport. ^[2] NTCP is found within the basolateral membrane hepatocytes. ^[3] The uptake of bile salts into the liver also allow for drugs and fat soluble vitamins to be both absorbed and excreted in the small intestine. NTCP also acts as a receptor for Hepatitis B virus (HBV) and Hepatitis D virus (HDV) which infect human livers through endocytosis when bound. The myristoylated (myr) domain of HBV, specifically residues 8-17, is critical for its binding to NTCP which halts the uptake of bile salts, indicating that HBV/HDV bind to NTCP at the same site as bile salts. ^[1]

Figure 2. Bile Salt Structure.

Structural Overview

NTCP has 9 transmembrane alpha helices (TM) that form the protein, with an extracellular N-terminus and intracellular C-terminus. NTCP has two domains within the protein, , made up of TM1, TM5, and TM6, and , made up of TM2-4 and TM7-9. An interesting feature of NTCP is the cross of TM3 and TM8 that form an within the protein. The two domains are essential to the conformation change of NTCP to bind bile salts ^[4].

There are two significant areas in the NTCP structure that facilitate ligand binding, which are referred to as "patches." Residues 84-87 of NTCP are patch 1, which are located on the TM2-TM3 loop in the core domain. This is also considered the extracellular region of NTCP “tunnel." Residues 157-165 NTCP are associated with patch 2. They are located on N-terminal half of the TM5 in the panel domain (residue sequence: KGIVISLVL). Patch 2 is also located in th extracellular region. These residues' importance was determined through mutations of these residues and examined through pull-down assays ^[3].

Binding Pocket

. The binding pocket forms a tunnel structure within NTCP at the interface of two domains that connects the external cytoplasm of the hepatocyte to the basolateral membrane. The face of the tunnel where the bile salts bind is lined with hydrophilic residues, whereas the opposite face of the transmembrane helices is hydrophobic, making the tunnel amphipathic. ^[5] The hydrophilic tunnel allows hydrophilic bile salts and sodium ions to be transported across the hydrophobic cell membrane. In the with no bile salt bound to the tunnel, it forms a hollow hole in the middle of the structure. When bile salts bind within, these bile salts completely occlude the .

Figure 2. Surface representation of the NTCP molecule with both patches shown. Patch 1 can be seen on the left side of the molecule, whereas patch 2 is located on the right side within the binding tunnel. [PDB file 7ZYI].

Conformation Change

Figure 3. Cartoon of NTCP topology.

The conformational change of NTCP's core domain helices are essential to bile salt binding and uptake. Figure 1 displays the topology of NTCP, highlighting both the panel (shown in blue) and core (shown in purple and pink) domains ^[4]. Helices 3 and 8 are the main structural components of the conformational change. Before bile salt can bind, the pore in which salt binds must be . The pore is flipped toward the outer membrane to allow for binding. Once , the pore is , and bile salt is able to be released into the cell, past the inner membrane.

Mechanism

Figure 4. Bile Salt Uptake Mechanism.

The NTCP protein goes through a conformational change when assisting in the uptake of bile salt into the cell. This is accomplished through the opening of a wide transmembrane pore, creating a transport pathway for bile salts. The mechanism includes two metal ions that allow for residue stabilization when going through the conformational change. Binding of the preS1 region of the HBV/HDV virus blocks any subsequent bile salt uptake. Thus, preS1 binding blocks the conformational change and entry of any salts into the cell. Residues 8-17 of preS1 are critical for NTCP:pres1 binding. Patch 1 and Patch 2 (external) residues interact with residues 8-17 of preS1 to facilitate binding.

Significance

NTCP is a key player in the absorption and digestion of fats and fat-soluble vitamins in the body, as well as the synthesis of bile within the liver. The uptake of bile salts, transcriptional and post-transcriptional, are signaling molecules for the liver and intestine. Bile salt, the transporting molecule of NTCP, aids in the absorption of lipophilic nutrients and vitamins in the small intestine. Additionally, bile salt plays a role in the endocrine system, excretion of toxins, and cholesterol maintenance. ^[1]. Thus, the significance of NTCP lies with the importance of bile salts; NTCP is necessary in maintaining bile salt levels and thus necessary in maintaining the aforementioned biological processes.

Bile Salt Uptake

Cirrhosis, commonly known as the last stage of liver disease, is due to a deficiency in the bile acid supply in the liver. Bile acid pools, as defined by Vlahcevic, are the negatively-charged precursors to bile and often are conjugated to positively-charged bile salts. This is attributed either a decrease in the production of bile salts or a large increase in the excretion of this molecule out of the cell. https://www.gastrojournal.org/article/S0016-5085(71)80053-7/pdf Cirrhosis causes symptoms such as jaundice, abdominal pain and swelling, and swelling of the legs and feet. A patient who has type two diabetes, men, and those who have or do abuse alcohol are also more sustainable to developing Cirrhosis. This diagnosis can lead to liver failure and other life-threatening diseases, making bile salt uptake essential to liver function. https://www.niddk.nih.gov/health-information/liver-disease/cirrhosis/definition-facts

References

↑ ^1.0 ^1.1 ^1.2 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.
↑ Maldonado-Valderrama, J., Wilde, P., Macierzanka, A., & Mackie, A. (2011). The role of bile salts in digestion. Advances in colloid and interface science, 165(1), 36–46. DOI: 10.1016/j.cis.2010.12.002.
↑ ^3.0 ^3.1 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.
↑ ^4.0 ^4.1 Xiangbing Qi, Wenhui Li. (2022). Unlocking the secrets to human NTCP structure. The Innovation, Vol. 3, Issue 5. 100294, ISSN 2666-6758, DOI: 10.1016/j.xinn.2022.100294.
↑ 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). DOI: 10.1038/s41422-022-00680-4.

Retrieved from "http://52.214.119.220/wiki/index.php/Sandbox_Reserved_1783"

@@ Line 4: / Line 4: @@
 == Background ==
-[[Image:CARTOON.png|400 px|right|thumb|'''Figure 1.''' NTCP structure with both Na ions and bile salts bound. PDB file 7ZYI.]]
+[[Image:Fig_1.png|400 px|right|thumb|'''Figure 1.''' NTCP structure with both Na+ ions and bile salts bound with the NTCP molecule shown in light blue, the two Na+ ions shown in purple spheres, and the bile salts shown in sticks as dark blue. [PDB file 7ZYI].]]
-Sodium taurocholate co-transporting polypeptide (NTCP) is a sodium-dependent transporter in the body that is responsible for the transportation of bile salts from the blood into epithelial liver cells. This carrier protein is responsible for a conformational change that allows bile salts to cross the cell membrane and enter the inside of liver cells. <Ref> 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). [https://doi.org/10.1038/s41586-022-04723-z DOI: 10.1038/s41586-022-04723-z]. </Ref>. Both sodium ions and bile salts bind to NTCP in the same binding pocket on the molecule (Fig. 1).
-NTCP also acts as a receptor for Hepatitis B virus and Hepatitis D virus. The bile salts transported by NTCP are located within the gastrointestinal tract of the body and play a very key role in many biological functions. These functions include digesting and absorbing nutrients by helping break down fats and transporting lipid soluble nutrients into the liver. <Ref> Maldonado-Valderrama, J., Wilde, P., Macierzanka, A., & Mackie, A. (2011). The role of bile salts in digestion. Advances in colloid and interface science, 165(1), 36–46. [https://doi.org/10.1016/j.cis.2010.12.002 DOI: 10.1016/j.cis.2010.12.002]. </Ref>. The NTCP carrier protein itself can be found within hepatocytes, or the epithelial cells of the liver, but more specifically, within the basolateral membrane of these cells. <Ref name="Asami"> 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. [https://dx.doi.org/10.1038/s41586-022-04845-4 DOI: 10.1038/s41586-022-04845-4]. </Ref>. The uptake of bile salts into the liver also allow for drugs to be both absorbed and excreted, as well as essential nutrients such as Vitamin A,D,E, and K to be absorbed in the small intestine.
+*Sodium taurocholate co-transporting polypeptide (NTCP) is a sodium-dependent transporter that is responsible for the transportation of bile salts from the blood into epithelial liver cells. <Ref name="Goutam"> 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). [https://doi.org/10.1038/s41586-022-04723-z DOI: 10.1038/s41586-022-04723-z]. </Ref> NTCP is a secondary active transport molecule that couples the thermodynamically favorable movement of Na+ ions with the unfavorable transport of bile salts into the cell (Fig. 1).
+*The bile salts transported by NTCP in the gastrointestinal tract are involved in digestion, nutrient absorption, fat breakdown, and lipid soluble nutrient transport. <Ref> Maldonado-Valderrama, J., Wilde, P., Macierzanka, A., & Mackie, A. (2011). The role of bile salts in digestion. Advances in colloid and interface science, 165(1), 36–46. [https://doi.org/10.1016/j.cis.2010.12.002 DOI: 10.1016/j.cis.2010.12.002]. </Ref> NTCP is found within the basolateral membrane hepatocytes. <Ref name="Asami"> 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. [https://dx.doi.org/10.1038/s41586-022-04845-4 DOI: 10.1038/s41586-022-04845-4]. </Ref> The uptake of bile salts into the liver also allow for drugs and fat soluble vitamins to be both absorbed and excreted in the small intestine. NTCP also acts as a receptor for Hepatitis B virus (HBV) and Hepatitis D virus (HDV) which infect human livers through endocytosis when bound. The myristoylated (myr) <scene name='95/952711/Pres1_binding_area_on_ntcp/3'>pre-S1</scene> domain of HBV, specifically residues 8-17, is critical for its binding to NTCP which halts the uptake of bile salts, indicating that HBV/HDV bind to NTCP at the same site as bile salts. <ref name="Goutam"/>
 [[Image:Bile Salt structure.png|300 px|left|thumb|'''Figure 2.''' Bile Salt Structure.]]
@@ Line 19: / Line 20: @@
 === Binding Pocket ===
-The NTCP binding pocket represents a "tunnel" lined with hydrophilic residues within the NTCP structure to allow hydrophilic bile salts and sodium ions to bind. When there are no bile salts bound to NTCP's binding tunnel, it forms a hollow hole in the middle of the structure, from <scene name='95/952710/Tunnel_front/1'>front</scene> to <scene name='95/952710/Tunnel_front/3'>back</scene>. As bile salts bind to this binding pocket, the bile salts very nicely fill the hole within NTCP and fit almost perfectly within the tunnel, to the point where the <scene name='95/952710/Bile_bound_to_tunnel/2'>tunnel</scene> can no longer be seen, as it is completely encompassing the bile salts. <scene name='95/952711/Sodium_residue_zoom_in_nctp/1'>Sodium binds to specific residues within the molecule. </scene> This tunnel formed connects the external cytoplasm of the hepatocyte to the inner leaflet of the basolateral membrane. The side of the tunnel where the bile salts bind are lined with hydrophilic residues, whereas the opposite side of the helix is lined with hydrophobic residues, as the transmembrane helices are amphipathic. <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 DOI: 10.1038/s41422-022-00680-4]. </Ref>.
+*<scene name='95/952711/Sodium_residue_zoom_in_nctp/1'>Sodium binds to residues 84-87 and 157-165 within NTCP </scene>. The binding pocket forms a tunnel structure within NTCP at the interface of two domains that connects the external cytoplasm of the hepatocyte to the basolateral membrane. The face of the tunnel where the bile salts bind is lined with hydrophilic residues, whereas the opposite face of the transmembrane helices is hydrophobic, making the tunnel amphipathic. <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 DOI: 10.1038/s41422-022-00680-4]. </Ref> The hydrophilic tunnel allows hydrophilic bile salts and sodium ions to be transported across the hydrophobic cell membrane. In the <scene name='95/952710/Tunnel_front/1'>outward facing state</scene> with no bile salt bound to the tunnel, it forms a hollow hole in the middle of the structure. When bile salts bind within, these bile salts completely occlude the <scene name='95/952710/Bile_bound_to_tunnel/2'>tunnel</scene>.
-[[Image:Patches.png|300 px|left|thumb|'''Figure 2.''' Surface representation of the NTCP molecule with both patches shown. Patch 1 can be seen on the left side of the molecule, whereas patch 2 is located on the right side within the binding tunnel. PDB file 7ZYI.]]
-The binding pocket of NTCP contains two patches on its exterior. These two patches are used for assisting in the binding of bile salts into the binding tunnel. These external patches are extremely important for aiding in the transport of bile salts from the exterior of NTCP to the interior binding tunnel <ref name="Asami"/>. Patch 1 is made up of residues 84-87 of NTCP and Patch 2 consists of residues 157-165. Patch 1 is located on the poles of NTCP, namely the top of the structure, within the TM2-TM3 transmembrane loop, whereas patch 2 is located towards the middle of the NTCP molecule within transmembrane 5 (TM5). These two patches are also predominantly responsible for binding the preS1 binding region of the HBV/HDV virus. Patch 2 also forms a part of the binding tunnel previously mentioned <ref name="Asami"/>.
+[[Image:Patches.png|300 px|left|thumb|'''Figure 2.''' Surface representation of the NTCP molecule with both patches shown. Patch 1 can be seen on the left side of the molecule, whereas patch 2 is located on the right side within the binding tunnel. [PDB file 7ZYI].]]
 === Conformation Change ===
@@ Line 39: / Line 39: @@
 == Significance ==
-NTCP is a key player in the absorption and digestion of fats and fat-soluble vitamins in the body, as well as the synthesis of bile within the liver. The uptake of bile salts, transcriptional and post-transcriptional, are signaling molecules for the liver and intestine. Bile salt, the transporting molecule of NTCP, aids in the absorption of lipophilic nutrients and vitamins in the small intestine. Additionally, bile salt plays a role in the endocrine system, excretion of toxins, and cholesterol maintenance. ADD GOUTAM REFERENCE HERE. Thus, the significance of NTCP lies with the importance of bile salts; NTCP is necessary in maintaining bile salt levels and thus necessary in maintaining the aforementioned biological processes.
+NTCP is a key player in the absorption and digestion of fats and fat-soluble vitamins in the body, as well as the synthesis of bile within the liver. The uptake of bile salts, transcriptional and post-transcriptional, are signaling molecules for the liver and intestine. Bile salt, the transporting molecule of NTCP, aids in the absorption of lipophilic nutrients and vitamins in the small intestine. Additionally, bile salt plays a role in the endocrine system, excretion of toxins, and cholesterol maintenance. <ref name="Goutam"/>. Thus, the significance of NTCP lies with the importance of bile salts; NTCP is necessary in maintaining bile salt levels and thus necessary in maintaining the aforementioned biological processes.
 === Bile Salt Uptake ===
@@ Line 45: / Line 45: @@
 Cirrhosis, commonly known as the last stage of liver disease, is due to a deficiency in the bile acid supply in the liver. Bile acid pools, as defined by Vlahcevic, are the negatively-charged precursors to bile and often are conjugated to positively-charged bile salts. This is attributed either a decrease in the production of bile salts or a large increase in the excretion of this molecule out of the cell. https://www.gastrojournal.org/article/S0016-5085(71)80053-7/pdf Cirrhosis causes symptoms such as jaundice, abdominal pain and swelling, and swelling of the legs and feet. A patient who has type two diabetes, men, and those who have or do abuse alcohol are also more sustainable to developing Cirrhosis. This diagnosis can lead to liver failure and other life-threatening diseases, making bile salt uptake essential to liver function. https://www.niddk.nih.gov/health-information/liver-disease/cirrhosis/definition-facts
-=== HBV/HDV ===
-Hepatitis B and D both rely on NTCP to bind and infect the human liver. HBV/HDV uses a the same patches as bile salt uptake within NTCP to infect the liver through endocytosis. The myristoylated (myr) pre-S1 domain of HBV is critical for its binding within the protein. Residues 8-17 within the <scene name='95/952711/Pres1_binding_area_on_ntcp/3'>pre-S1</scene> domain were found to be most important in pre-S1 binding to NTCP. HBV/HDV binding halts the uptake of bile salt, indicating that the tunnel formed within NTCP allows the uptake of bile salts and may also mediate the binding of HBV/HDV. [[https://www.nature.com/articles/s41586-022-04845-4]]
 </StructureSection>
 == References ==
 <references/>

Sandbox Reserved 1783

From Proteopedia

Revision as of 19:52, 10 April 2023

Sodium Taurocholate Co-Transporting Peptide

Contents

Background

Structural Overview

Binding Pocket

Conformation Change

Mechanism

Significance

Bile Salt Uptake

References

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