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CCR5 N-terminal region plays a critical role in HIV-1 inhibition by Toxoplasma gondii-derived cyclophilin-18

Golding, H; Khurana, S; Yarovinsky, F; King, L R; Abdoulaeva, G; Antonsson, Liselotte LU ; Owman, Christer LU ; Platt, EJ; Kabat, D and Andersen, J F, et al. (2005) In Journal of Biological Chemistry 280(33). p.29570-29577
Abstract
Molecular mimicry of chemokine ligands has been described for several pathogens. Toxoplasma gondii produces a protein, cyclophilin-18 (C-18), which binds to the human immunodeficiency virus (HIV) co-receptor CCR5 and inhibits fusion and infection of T cells and macrophages by R5 viruses but not by X4 viruses. We recently identified structural determinants of C-18 required for anti-HIV activity (Yarovinsky, F., Andersen, J. F., King, L. R., Caspar, P., Aliberti, J., Golding, H., and Sher, A. ( 2004) J. Biol. Chem. 279, 53635 - 53642). Here we have elucidated the fine specificity of CCR5 residues involved in binding and HIV inhibitory potential of C-18. To delineate the regions of CCR5 involved in C-18 binding, we analyzed C-18 inhibition of... (More)
Molecular mimicry of chemokine ligands has been described for several pathogens. Toxoplasma gondii produces a protein, cyclophilin-18 (C-18), which binds to the human immunodeficiency virus (HIV) co-receptor CCR5 and inhibits fusion and infection of T cells and macrophages by R5 viruses but not by X4 viruses. We recently identified structural determinants of C-18 required for anti-HIV activity (Yarovinsky, F., Andersen, J. F., King, L. R., Caspar, P., Aliberti, J., Golding, H., and Sher, A. ( 2004) J. Biol. Chem. 279, 53635 - 53642). Here we have elucidated the fine specificity of CCR5 residues involved in binding and HIV inhibitory potential of C-18. To delineate the regions of CCR5 involved in C-18 binding, we analyzed C-18 inhibition of cells expressing CXCR4/CCR5 chimeric receptors and CCR5 with a truncated N terminus (Delta 2-19). These experiments identified a critical role for the N terminus of CCR5 in C-18 binding and anti-HIV activity. Studies with a large panel of CCR5 N-terminal peptides, including Tyr-sulfated analogues, truncated peptides, and alanine-scanning mutants, suggested that each of the 12 - 17 amino acids in the N terminus of CCR5 are essential for C-18 binding and inhibitory activity. Tyr sulfation did not improve C-18 reactivity. This finding is of interest because the same CCR5 N-terminal region was shown previously to play a key role in binding of HIV-1 envelope glycoproteins. The elucidation of the functional C-18-binding mechanism may help in the rational design of novel antiviral agents against HIV. (Less)
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Journal of Biological Chemistry
volume
280
issue
33
pages
29570 - 29577
publisher
ASBMB
external identifiers
  • wos:000231176200024
  • scopus:23844481085
ISSN
1083-351X
DOI
10.1074/jbc.M500236200
language
English
LU publication?
yes
id
2164f837-0378-45f6-9dd2-47dfa1492a8f (old id 227517)
date added to LUP
2007-08-07 13:22:14
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2017-04-30 10:00:44
@article{2164f837-0378-45f6-9dd2-47dfa1492a8f,
  abstract     = {Molecular mimicry of chemokine ligands has been described for several pathogens. Toxoplasma gondii produces a protein, cyclophilin-18 (C-18), which binds to the human immunodeficiency virus (HIV) co-receptor CCR5 and inhibits fusion and infection of T cells and macrophages by R5 viruses but not by X4 viruses. We recently identified structural determinants of C-18 required for anti-HIV activity (Yarovinsky, F., Andersen, J. F., King, L. R., Caspar, P., Aliberti, J., Golding, H., and Sher, A. ( 2004) J. Biol. Chem. 279, 53635 - 53642). Here we have elucidated the fine specificity of CCR5 residues involved in binding and HIV inhibitory potential of C-18. To delineate the regions of CCR5 involved in C-18 binding, we analyzed C-18 inhibition of cells expressing CXCR4/CCR5 chimeric receptors and CCR5 with a truncated N terminus (Delta 2-19). These experiments identified a critical role for the N terminus of CCR5 in C-18 binding and anti-HIV activity. Studies with a large panel of CCR5 N-terminal peptides, including Tyr-sulfated analogues, truncated peptides, and alanine-scanning mutants, suggested that each of the 12 - 17 amino acids in the N terminus of CCR5 are essential for C-18 binding and inhibitory activity. Tyr sulfation did not improve C-18 reactivity. This finding is of interest because the same CCR5 N-terminal region was shown previously to play a key role in binding of HIV-1 envelope glycoproteins. The elucidation of the functional C-18-binding mechanism may help in the rational design of novel antiviral agents against HIV.},
  author       = {Golding, H and Khurana, S and Yarovinsky, F and King, L R and Abdoulaeva, G and Antonsson, Liselotte and Owman, Christer and Platt, EJ and Kabat, D and Andersen, J F and Sher, A},
  issn         = {1083-351X},
  language     = {eng},
  number       = {33},
  pages        = {29570--29577},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {CCR5 N-terminal region plays a critical role in HIV-1 inhibition by Toxoplasma gondii-derived cyclophilin-18},
  url          = {http://dx.doi.org/10.1074/jbc.M500236200},
  volume       = {280},
  year         = {2005},
}