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. 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.

Function

Bile Salt Uptake

HBV/HDV Infection

Structure

Proline/Glycine Hinge

Core & Panel Domains

Sodium Binding Sites

Significant Residues

The vast majority of residues involved in bile salt uptake are also involved in HBV/HDV infection. (extracellular view) of Human NTCP have been shown to be vital for preS1 domain recognition along with bile salt uptake. These residues were replaced in mouse NTCP by human NTCP and conferred to successful binding of the virus. These residues are found in the extracellular loop connecting TM2 and TM3. (extracellular view) have also been shown to be vital for preS1 recognition and bile salt uptake. These residues were mutated in monkey NTCP to the human residues and preS1 binding was then successful. These residues are found on the N-terminal end of TM5. The absence of residues in either of these hinders preS1 binding and therefore HBV/HDV infection. Interestingly, residues 84-87 do not affect bile acid uptake, so it is a potential site for blocking HBV/HDV infection while maintaining NTCP's ability to perform its normal function. Another important residue was discovered to be a single-nucleotide polymorphism in a small population in East Asia. , which is normally serine, being mutated to phenylalanine prevents preS1 binding and does not support bile acid transport. This residue is also found extracellularly, on TM8 of NTCP.

Molecular Mechanism

Mechanism of Bile Salt Uptake

Mechanism of HBV/HDV Infection

HBV/HDV infection is reliant on multiple properties that must be present on both the virus itself and the NTCP protein. First, the HBV/HDV capsid must be myristoylated in order for proper recognition by NTCP. Residues 2-48 are the most significant residues of HBV/HDV that are highly conserved amongst these viruses that are vital for infection. Specifically, residues 8-17 on HBV/HDV have been identified as the most important. These residues are NPLGFFPDHQ. There are two proposed mechanisms as to how exactly HBV/HDV bind to NTCP and enter the cell. In both mechanisms, there is an initial translocation of the myristoylated preS1 HBV/HDV virus to interact with the host cell (hepatocyte). The first mechanism involves the myristoyl group of preS1 binding to the host cell membrane, not NTCP, and residues P8-H17 interacting with NTCP residues 157-165. The second mechanism involves the myristoyl group of preS1 binding directly into the open-pore of NTCP interacting with residues 157-165. In both proposed mechanisms, the interactions with the extracellular residues 84-87 of NTCP is unknown.

Medical Relevance

Relevance

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