Distinct but overlapping epitopes for the interaction of a CC-chemokine with CCR1, CCR3 and CCR5
- PMID: 9289016
- DOI: 10.1021/bi970593z
Distinct but overlapping epitopes for the interaction of a CC-chemokine with CCR1, CCR3 and CCR5
Abstract
Chemokines play an important role in inflammation. The mechanism via which they bind to more than one receptor and activate them is not well understood. The chemokines are thought to interact with their receptors via two distinct sites, one necessary for binding and the other for activation of signal transduction. In this study we have used alanine scanning mutagenesis to identify residues on RANTES that specifically interact with its receptors CCR1, CCR3, and CCR5 for binding and activation. Residues within a potential receptor binding site known as the N-loop (residues 12-20) and near the N-terminus of RANTES were individually mutated to alanine. The results of this study show that, within the N-loop, the side chain of R17 is necessary for RANTES binding to CCR1, F12 for binding to CCR3, and F12 and I15 for binding to CCR5, thus forming distinct but overlapping binding epitopes. In addition, our finding that P2 is necessary for binding to CCR5 is the first to show that a residue near the N-terminus of a CC-chemokine is involved in binding to a receptor. We have also found that P2, D6, and T7 near the N-terminus are involved in activating signal transduction via CCR1, P2 and Y3 via CCR3, and Y3 and D6 via CCR5. These results indicate that RANTES interacts with each of its receptors in a distinct and specific manner and provide further evidence to support the two-site model of interaction between chemokines and their receptors.
Similar articles
-
Molecular anatomy of CCR5 engagement by physiologic and viral chemokines and HIV-1 envelope glycoproteins: differences in primary structural requirements for RANTES, MIP-1 alpha, and vMIP-II Binding.J Mol Biol. 2001 Nov 9;313(5):1181-93. doi: 10.1006/jmbi.2001.5086. J Mol Biol. 2001. PMID: 11700073
-
A chimeric MIP-1alpha/RANTES protein demonstrates the use of different regions of the RANTES protein to bind and activate its receptors.J Leukoc Biol. 2001 Jun;69(6):977-85. J Leukoc Biol. 2001. PMID: 11404385
-
Nonproductive human immunodeficiency virus type 1 infection of human fetal astrocytes: independence from CD4 and major chemokine receptors.Virology. 1999 Nov 25;264(2):370-84. doi: 10.1006/viro.1999.9998. Virology. 1999. PMID: 10562499
-
New therapeutics that modulate chemokine networks.Nat Rev Drug Discov. 2002 May;1(5):347-58. doi: 10.1038/nrd795. Nat Rev Drug Discov. 2002. PMID: 12120410 Review.
-
Therapeutic potential of chemokine receptor antagonists for liver disease.Expert Rev Clin Pharmacol. 2011 Jul;4(4):503-13. doi: 10.1586/ecp.11.24. Expert Rev Clin Pharmacol. 2011. PMID: 22114859 Review.
Cited by
-
Production of an aberrant splice variant of CCL5 is not caused by genetic mutation in the mammary glands of mastitis‑infected Holstein cows.Mol Med Rep. 2019 May;19(5):4159-4166. doi: 10.3892/mmr.2019.10103. Epub 2019 Mar 28. Mol Med Rep. 2019. PMID: 30942444 Free PMC article.
-
A new monoclonal antibody, mAb 4A12, identifies a role for the glycosaminoglycan (GAG) binding domain of RANTES in the antiviral effect against HIV-1 and intracellular Ca2+ signaling.J Exp Med. 1998 Nov 16;188(10):1917-27. doi: 10.1084/jem.188.10.1917. J Exp Med. 1998. PMID: 9815269 Free PMC article.
-
The solution structure of the anti-HIV chemokine vMIP-II.Protein Sci. 1999 Nov;8(11):2270-80. doi: 10.1110/ps.8.11.2270. Protein Sci. 1999. PMID: 10595530 Free PMC article.
-
Control of feeding behavior in C. elegans by human G protein-coupled receptors permits screening for agonist-expressing bacteria.Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14826-31. doi: 10.1073/pnas.0803290105. Epub 2008 Sep 24. Proc Natl Acad Sci U S A. 2008. PMID: 18815363 Free PMC article.
-
Kinetic and thermodynamic studies reveal chemokine homologues CC11 and CC24 with an almost identical tertiary structure have different folding pathways.BMC Biophys. 2017 Sep 12;10:7. doi: 10.1186/s13628-017-0039-4. eCollection 2017. BMC Biophys. 2017. PMID: 28919974 Free PMC article.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials
Miscellaneous
