Identification of new interaction partners of the human ABC transporter MDR3

Excerpt

The human multidrug resistance protein 3 (MDR3/ABCB4) belongs to the ATP binding cassette (ABC) transporter family found in all kingdoms of life. MDR3 is located in the canalicular membrane of hepatocytes and translocates phosphatidylcholine (PC) from the inner to the outer leaflet of the canalicular membrane energized by ATP hydrolysis. PC is one major component of bile and is essential to protect the biliary duct from bile salts, which are translocated by the bile salt export pump (BSEP/ABCB11). Phosphatidylcholine, bile salts and cholesterol translocated by ABCG5/G8 form mixed micelles. These mixed micelles have a lower capacity to extract lipids from the membrane and prevent the crystallization of cholesterol in the biliary duct. Different types of liver diseases e.g. progressive familial intrahepatic cholestasis type 3 (PFIC 3) are caused by dysfunction of MDR3. On the one hand mutations within the MDR3 gene can abolish the ATPase activity and PC lipid transport, respectively. On the other hand defects of the regulation pathway with respect to the targeting and retention of MDR3 to the canliculare membrane can occur. Currently, it is not known, how MDR3 is regulated and targeted to the canalicular membrane. Further, MDR3 shares over 75 % identity with the multidrug resistance protein 1 (MDR1/ABCB1). MDR1 is well-characterized and plays an enormous challenge in chemotherapy. If we identify the regulation mechanism of MDR3, we will as well contribute to the understanding of MDR1 regulation. …