Brief Critical Reviews
February 7992: 47-57
A Retrovirus Uses a Cationic Amino Acid Transporter as a Cell Surface Receptor New studies have indicated that the cell membrane receptor for the ecotropic murine leukemia virus is the classic membrane amino acid transporter y +,the principal transporter of cationic L-acids in mammalian cells. This finding has been hailed as a landmark in cell physiology which may reveal new mechanisms of viral pathogenesis. These studies represent the first amino acid transporter to be cloned, as well as the first example of a virus subverting a transmembrane protein as a receptor.
Physiologically, the amino acid transport system y serves most conspicuously for transport of the essential cationic amino acids, including lysine, histidine, and arginine. The nutritional importance of the transport system is obvious, since this system participates in epithelial absorption’ as well as in other interorgan amino acid flows. Interactions are also seen between cationic and dipolar amino acids in the rabbit ileum.’ We are most familiar with amino acids in their zwitterionic or dipolar forms (sometimes less cautiously called neutral through an unfortunate algebraic addition attributable to a deplorable disregard of the dipoles). The letter Z (for zwitterion) stands conventionally for the transport systems selective for zwitterionic amino acids, and X and Y stand respectively for the transport systems for the anionic and cationic amino acids.3 Examples of such amino acids are aspartate and lysine. Lysine is classified as cationic, rather than the more familiar basic. or diamino, to obviate a dangerous source of confusion: even at neutral pH enough lysine is present in a dipolar form to make it appreciably an inhibitor of transport of the dipolar amino acid, leucine. Wherever it is shown that a transporter selects for transport of lysine molecules with the usual cationic or tripolar character, that selective feature of the transport system is emphasized by adding a superscript plus sign, thus: y + . +
This review was prepared by Halvor H. Christensen, Ph.D., at the Department of Pediatrics, University of California at San Diego, La Jolla, CA 92093. Nutrition Reviews, Vol. 50, No. 2
One more detail of the y + transporter needs emphasis, namely that it has a sodium ion sensitivity so low that we may refer to it as a Na+-independent transporter. Conventionally, that independence is indicated by using the lower-case letter in the symbol Y + . ~However, in the late 1960s a peculiar sensitivity of system y + to the sodium ion concentration was u n ~ o v e r e d . ~It~was ’ found that a special group of dipolar amino acids were able to inhibit the transport of lysine cation and its analogs only if enough of the otherwise unnecessary Na+ was present. It turned out that these amino acids were transported by system y + along with a sodium ion serving as a cosubstrate. It was possible to show also in yeast Saccaromyces cerevisiae6 that the sodium ion served as a surrogate for the terminal cationic group found in the more usual amino acid substrates of the y + amino acid transporter. Furthermore, the dipolar amino acids with this ability to cooperate conspicuously with Na+ for transport proved to be ones that have a hydroxyl or carbonyl group terminal to a four- to six-carbon chain (e.g., homoserine, pentahomoserine, glutamine) in a manner that pointed to a role for the cosubstrate Na+ in bonding to the oxygen atom present in these terminal groups. However, if the amino acid chain was as short as that of serine, this effect of Na+ became quite small. This paradoxical feature of “sodiumdependent transport via a sodium-independent sysseems so far to present its greatest biological importance in offering us information as to how transporters manage in general to recognize their amino acid substrates. Somewhere functional roles for this system in dipolar amino acid migrations, for example in glutamine transport, seems likely yet to be found. More important, may we not also expect discoveries of relations of various other transporters to other distinct membrane functions? Viruses exploit cell-surface molecules as receptors for bonding to and entry into host cells. Cellsurface antigens have often been identified by the ability of corresponding antibodies to block viral attachment or infectivity. In addition, DNA transfer studies have been used to identify genes which confer virus infectivity. In other cases the DNA transfection approach has brought attention to other47
wise-unrecognized receptor molecules. Recent studies7*’of the ecoR gene, which codes for the receptor of the ecotropic murine leukemia virus, have discovered that the receptor molecule is most likely the classic y + amino acid transporter. This gene encodes a protein of 622 amino acid residues with 14 domains with potentially membranespanning characteristics. This transmembrane topology was similar to several membrane transporter proteins, especially ones for arginine and histidine in yeast. This clue led groups in Boston, Massachu~ e t t sand , ~ Portland, Oregon,’ to search for a similar transport function of the ecoR murine leukemia virus receptor. Each of these groups has now shown7,’ that Xenopus oocytes injected with ecoR messenger RNA show increased amino acid uptake corresponding closely to the ubiquitous system y +.These findings are exciting because they represent the first mammalian amino acid transporter to be cloned and the first instance of a virus subverting a transmembrane transport protein as a receptor.’ Suppose one had been asked to choose an amino acid transport system advantageous and challenging for discovering how its transporter might serve such apparently unrelated functions as amino acid transporter and viral receptor. What better choice could have been offered than system y + with its distinctive characteristics? The known properties of the amino acid transporter suggest that the concentration of Na+ and of other cations may affect viral receptor function. Opportunities are now available to look for other plausible and revealing interactions between these two distinct membrane functions. Moreover, as pointed out by Kim et al.,7 “these findings raise the possibility that changes in the nutritional or hormonal state of the host which influence amino acid metabolism could alter receptor expression and thereby change susceptibility to ecotropic retrovirus infection.” Without reaching more than a preliminary conclusion, Wang et a1.*
raise the question whether the binding of the virus perturbs amino acid transport via this important system. Such a perturbing effect could contribute to known nutritional problems in virus infections, and becomes plausible if the site at which the virus binds to the protein should lie within or near the domain serving for metabolite transport. These authors’ point out that resulting transport abnormalities might contribute to disease consequences including faulty immunogenesis, hemolytic anemia, and neuronal degeneration, thereby adding to the knowledge of viral pathogenesis. 1. Sepulveda FV, Pearson JD. Cationic amino acid transport by two renal epithelial cell lines, LLC-PK1 and MDCK. J Cell Physiol 1985;123:144-50 2. Munck BG. Transport of neutral and cationic amino acids across the brush-border membranes of the rabbit ileum. J Memb Biol 1985;83:1-13 3. Bannai S,et al. Amino acid transport systems. Nature 1984;311:308 4. Christensen HN, Antonioli JA. Cationic amino acid transport in the rabbit reticulocyte: Na+-dependent inhibition of Na+-independent transport. J Biol Chem 1969;244:1497-1504 5. Christensen HN, Handlogten ME, Thomas EL. Na+facilitated reactions of neutral amino acids with a cationic amino acid transport system. Proc Nat Acad Sci USA 1969;63:94&55 6. Thomas EL, Shao T-C, Christensen HN. Structural specificity in the interaction of neutral amino acids and alkali-metal ions with a cationic amino acid transport system. J Biol Chem 1971;246:1677-81 7. Kim JW, Closs El, Albritton LM, Cunningham JM. Transport of cationic amino acids by the mouse ecotropic retrovirus receptor. Nature 1991$52: 725-28 8. Wang H, Kavanaugh MP, North RA, Kabat D. Cellsurface receptor for ecotropic murine retroviruses is a basic amino acid transporter. Nature 1991;352: 729-31 9. Vile RG, Weiss RA. Virus receptors as permeases. Nature 1991;352:66&67
Zinc Plays Both Structural and Catalytic Roles in Metalloproteins Zinc is bound to the catalytic site of zincdependent hydrolases by three amino acid residues, commonly histidines and glutamic acid, and to the structural site of gene transcription regulators by cysteine and histidine. Site-
directed mutagenesis of even one catalytic-site ligand destroys enzyme activity without changing physical properties of the protein, including immunoreactivity. However, nutritional studies demonstrating loss of transcriptional activity upon zinc deprivation have not been reported.
This review was prepared by Boyd L. O’Dell, Ph.D., at the Department of Biochemistry, University of Missouri, Columbia, MO 6521 1.
As an essential component of metalloproteins, zinc plays a role in both catalysis and stabilization of structure. It has long been recognized that some
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Nutrition Reviews, Vol. 50, No. 2