Novel use of an osmolyte to dissect multiple thermodynamic linkages in a chemokine ligand-receptor system

Lavanya Rajagopalan, Jörg Rösgen, David Wayne Bolen, Krishna Rajarathnam

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

We have used trimethylamine N-oxide (TMAO), a protecting osmolyte, to dissect the complex thermodynamic linkages involved in the interaction between the chemokine interleukin-8 (IL-8) and the N-domain of its receptor CXCR1. Our results show that TMAO induces folding in the CXCR1 receptor N-domain and that the N-domain upon folding binds ligand with higher affinity. This represents, to our knowledge, the smallest domain that has been shown to be folded in osmolyte. Using the phase diagram method to analyze this thermodynamic relationship graphically, we also observe that TMAO favors ligand dimerization and that the dimeric ligand binds the receptor domain with lower affinity. We have thus been able to dissect coupling among three distinct processes, receptor domain folding, ligand dimerization, and ligand-receptor domain binding in this chemokine-receptor system. We also observe that the affinity of the related chemokine, melanoma growth stimulatory activity (MGSA), increases concurrent with N-domain folding similar to IL-8 but shows more profound differences on ligand dimerization. These studies establish a novel and innovative use of osmolytes to dissect linkages among different processes and exploit the phase diagram as a tool to graphically represent and dissect complex thermodynamic relationships in biological systems. On the basis of our observations and earlier work, we discuss the relevance of ligand dimerization in chemokine regulation.

Original languageEnglish (US)
Pages (from-to)12932-12939
Number of pages8
JournalBiochemistry
Volume44
Issue number39
DOIs
StatePublished - Oct 4 2005

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Chemokine Receptors
Thermodynamics
Chemokines
Ligands
Dimerization
Interleukin-8A Receptors
Interleukin-8
Phase diagrams
Biological systems
Melanoma
Growth
trimethyloxamine

ASJC Scopus subject areas

  • Biochemistry

Cite this

Novel use of an osmolyte to dissect multiple thermodynamic linkages in a chemokine ligand-receptor system. / Rajagopalan, Lavanya; Rösgen, Jörg; Bolen, David Wayne; Rajarathnam, Krishna.

In: Biochemistry, Vol. 44, No. 39, 04.10.2005, p. 12932-12939.

Research output: Contribution to journalArticle

Rajagopalan, Lavanya ; Rösgen, Jörg ; Bolen, David Wayne ; Rajarathnam, Krishna. / Novel use of an osmolyte to dissect multiple thermodynamic linkages in a chemokine ligand-receptor system. In: Biochemistry. 2005 ; Vol. 44, No. 39. pp. 12932-12939.
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