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P4-ATPase Atp8b1/FIC1: Structural features and physiological functions in health and disease

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Abstract

The P4 ATPase family of P-type ATPases is of especial interest, since the main function of P4 ATPases is the translocation of phospholipids, phosphatidylserine in particular, from the outer monolayer of the plasma membrane to the inner one. P4 ATPase isoforms are redundant to some extent, but structural defects of certain isoforms can still lead to rather severe pathologies at the whole-organism level due to tissue specificity of expression of the corresponding genes and variability of the intracellular localization of the proteins and regulatory pathways. The product of the gene ATP8B1 occupies a special place among P4 ATPases, since a number of point mutations in this gene are known to cause severe hereditary diseases, namely, two forms of hereditary cholestasis (Byler disease and benign recurrent intrahepatic cholestasis) with extrahepatic symptoms including sensorineural hearing loss, pneumonia, impaired function of the sweat glands, and growth retardation. The physiological functions of the protein Atp8b1/FIC1 were characterized to a certain extent; they consist in the translocation of certain phospholipids (phosphatidylserine and cardiolipin) from the outer monolayer of the plasma membrane to the inner one. Disturbance of membrane asymmetry due to insufficient activity of Atp8b1/FIC1 is known to result in loss of hair cells in the inner ear, disruption of transport of bile acids in hepatocytes, and liver cirrhosis. Insufficient activity of Atp8b1/FIC1 is likely to increase the susceptibility of the organism to bacterial infections. It should be noted that in vivo regulation pathways for Atp8b1/FIC1 activity have not yet been characterized in sufficient detail. Therefore, investigation of this protein holds promise for better understanding of molecular mechanisms underpinning the development of pathologies, as well as for identification of potential therapeutic targets.

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Abbreviations

PFIC1:

progressive familial intrahepatic cholestasis type 1

BRIC:

benign recurrent intrahepatic cholestasis

BA:

bile acids

PM:

plasma membrane

ER:

endoplasmic reticulum

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Authors and Affiliations

  1. Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia

    T. V. Korneenko, N. B. Pestov, I. A. Okkelman & M. I. Shakhparonov

  2. Department of Physiology and Pharmacology, University of Toledo, College of Medicine, Toledo, Ohio, USA

    N. N. Modyanov

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  1. T. V. Korneenko
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  2. N. B. Pestov
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  3. I. A. Okkelman
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  4. N. N. Modyanov
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  5. M. I. Shakhparonov
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Correspondence to M. I. Shakhparonov.

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Original Russian Text © T.V. Korneenko, N.B. Pestov, I.A. Okkelman, N.N. Modyanov, M.I. Shakhparonov, 2015, published in Bioorganicheskaya Khimiya, 2015, Vol. 41, No. 1, pp. 3–12.

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Korneenko, T.V., Pestov, N.B., Okkelman, I.A. et al. P4-ATPase Atp8b1/FIC1: Structural features and physiological functions in health and disease. Russ J Bioorg Chem 41, 1–9 (2015). https://doi.org/10.1134/S1068162015010070

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