Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0008370 (cholestasis)
 9,378 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Members of the P(4) family of P-type ATPases (P(4)-ATPases) are believed to function as phospholipid flippases in complex with CDC50 proteins. Mutations in the human class 1 P(4)-ATPase gene ATP8B1 cause a severe syndrome characterized by impaired bile flow (intrahepatic cholestasis), often leading to end-stage liver failure in childhood. In this study, we determined the specificity of human class 1 P(4)-ATPase interactions with CDC50 proteins and the functional consequences of these interactions on protein abundance and localization of both protein classes. ATP8B1 and ATP8B2 co-immunoprecipitated with CDC50A and CDC50B, whereas ATP8B4, ATP8A1, and ATP8A2 associated only with CDC50A. ATP8B1 shifted from the endoplasmic reticulum (ER) to the plasma membrane upon coexpression of CDC50A or CDC50B. ATP8A1 and ATP8A2 translocated from the ER to the Golgi complex and plasma membrane upon coexpression of CDC50A, but not CDC50B. ATP8B2 and ATP8B4 already displayed partial plasma membrane localization in the absence of CDC50 coexpression but displayed a large increase in plasma membrane abundance upon coexpression of CDC50A. ATP8B3 did not bind CDC50A and CDC50B and was invariably present in the ER. Our data show that interactions between CDC50 proteins and class 1 P(4)-ATPases are essential for ER exit and stability of both subunits. Furthermore, the subcellular localization of the complex is determined by the P(4)-ATPase, not the CDC50 protein. The interactions of CDC50A and CDC50B with multiple members of the human P(4)-ATPase family suggest that these proteins perform broader functions in human physiology than thus far assumed.
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PMID:Heteromeric interactions required for abundance and subcellular localization of human CDC50 proteins and class 1 P4-ATPases. 2094 5

P4-ATPases, a subfamily of P-type ATPases, were initially identified as aminophospholipid translocases in eukaryotic membranes. These proteins generate and maintain membrane lipid asymmetry by translocating aminophospholipids (phosphatidylserine and phosphatidylethanolamine) from the exoplasmic/lumenal leaflet to the cytoplasmic leaflet. The human genome encodes 14 P4-ATPases, and the cellular localizations, substrate specificities, and cellular roles of these proteins were recently revealed. Numerous P4-ATPases, including ATP8A1, ATP8A2, ATP11A, ATP11B, and ATP11C, transport phosphatidylserine. By contrast, ATP8B1, ATP8B2, and ATP10A transport phosphatidylcholine but not aminophospholipids, although there is a discrepancy regarding the substrate of ATP8B1 in the literature. Some yeast and plant P4-ATPases can also translocate phosphatidylcholine. At least 2 P4-ATPases (ATP8A2 and ATP8B1) are associated with severe human diseases, and other P4-ATPases are implicated in various pathophysiologic conditions in mouse models. Here, we discuss the cellular functions of phosphatidylcholine flippases and suggest a model for the phenotype of progressive familial intrahepatic cholestasis 1 caused by a defect in ATP8B1.-Shin, H.-W., Takatsu, H. Substrates of P4-ATPases: beyond aminophospholipids (phosphatidylserine and phosphatidylethanolamine).
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PMID:Substrates of P4-ATPases: beyond aminophospholipids (phosphatidylserine and phosphatidylethanolamine). 3050 29