Team:Freiburg/Content/Project/Receptor

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The AcCELLerator

murine cationic amino acid transporter 1 (mCAT-1)

Natural function

Transporters of the cationic amino acid transporter (CAT) family form a class of proteins that occur in mammalian cells as a subfamily of the solute carrier family 7 (SLC7). Expressed nearly ubiquitously in the body, they catalyze the bidirectional transport of cationic amino acids through the cell membrane including the essential amino acids lysine and arginine. [1] In several studies it was shown that this transporter is necessary for basic cell functions such as protein synthesis, nitric oxide synthesis and inter-organ amino acid flow. Additionally, it plays a key role in recovery after cell stress as it transports essential amino acids into the cell as soon as they become available again. The central importance of the CAT family becomes evident, if i.e. mCAT-1 (SLC7A1) is deleted by knock-out leading to death at the first day after birth.[2]

Structure

In terms of the structure of mCAT-1 it is predicted to exhibit 14 transmembrane domains with intracellular N- and C-terminus. Within the length of 622 amino acids, the third extracellular loop of the receptor is of greatest interest. This site serves as the entry point for the Murine Leukemia Virus (MuLV) and is highly variable between different species. Even close relatives to mice like rats or hamsters exhibit a different CAT-1 that cannot be used by the MuLV as a way in their cells. A reason for this variability of CAT-1 among different species could be a co-evolution of virus (MuLV) and host (mouse). [3] Changes in the part of the mouse genome coding for the third extracellular loop lead to a different structure of the receptor. [4] This change of the viral entry site prohibited viral infection of the mouse forcing the virus to adapt to these changes of CAT-1. As a consequence, the number of hosts of the virus decreased until different mouse species remained. [5]

Fig.1: Scheme of mCAT-1.

mCAT-1 as viral entry side

Found in the year 1989 [6], it was shown that in the presence of mCAT-1 on the surface of mouse cells these cells could be infected by the MuLV. Furthermore, in this publication the receptor of mouse cells was cloned into human cells creating a selective susceptibility to infection by MuLV. Following the lead, The AcCELLerator bases on the selective expression of mCAT-1 on human cells (HEK-293) after stimulation of a minimal promoter creating the viral entry point for MuLV.

  1. Kozak, C.A., Evolution of different antiviral strategies in wild mouse populations exposed to different gammaretroviruses. Curr Opin Virol, 2013. 3(6): p. 657-63.
  2. Hatzoglou, M., et al., Regulation of cationic amino acid transport: the story of the CAT-1 transporter. Annu Rev Nutr, 2004. 24: p. 377-99.
  3. Closs, E.I., et al., Structure and Function of Cationic Amino Acid Transporters (CATs). The Journal of Membrane Biology, 2006. 213(2): p. 67-77.
  4. Ferrarone, J., et al., Second site mutation in the virus envelope expands the host range of a cytopathic variant of Moloney murine leukemia virus. Virology, 2012. 433(1): p. 7-11.
  5. Kozak, C.A., Naturally Occurring Polymorphisms of the Mouse Gammaretrovirus Receptors CAT-1 and XPR1 Alter Virus Tropism and Pathogenicity. Advances in Virology, 2011. 2011: p. 16.
  6. Albritton, L.M., et al., A putative murine ecotropic retrovirus receptor gene encodes a multiple membrane-spanning protein and confers susceptibility to virus infection. Cell, 1989. 57(4): p. 659-666.

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