• Modulation of the CXC chemokine receptor 4 agonist activity of ubiquitin through C-terminal protein modification.

Modulation of the CXC chemokine receptor 4 agonist activity of ubiquitin through C-terminal protein modification.

Biochemistry (2013-05-24)
Abhishek Tripathi, Vikas Saini, Adriano Marchese, Brian F Volkman, Wei-Jen Tang, Matthias Majetschak

Extracellular ubiquitin has recently been described as a CXC chemokine receptor (CXCR) 4 agonist. Studies on the structure-function relationship suggested that the C-terminus of ubiquitin facilitates CXCR4 activation. It remains unknown, however, whether C-terminal processing of ubiquitin could be biologically relevant and whether modifications of the ubiquitin C-terminus can modulate CXCR4 activation. We show that C-terminal truncated ubiquitin antagonizes ubiquitin and stromal cell-derived factor (SDF)-1α induced effects on cell signaling and function. Reduction of cell surface expression of insulin degrading enzyme (IDE), which cleaves the C-terminal di-Gly of ubiquitin, enhances ubiquitin induced reduction of cAMP levels in BV2 and THP-1 cells, but does not influence changes in cAMP levels in response to SDF-1α. Reduction of cell surface IDE expression in THP-1 cells also increases the chemotactic activity of ubiquitin. As compared with native ubiquitin, C-terminal Tyr extension of ubiquitin results in reduced CXCR4 mediated effects on cellular cAMP levels and abolishes chemotactic activity. Replacement of C-terminal di-Gly of ubiquitin with di-Val or di-Arg enhances CXCR4 mediated effects on cAMP levels and the di-Arg substitution exerts increased chemotactic activity, when compared with wild type ubiquitin. The chemotactic activities of the di-Val and di-Arg mutants and their effects on cAMP levels can be antagonized with C-terminal truncated ubiquitin. These data suggest that the development of CXCR4 ligands with enhanced agonist activities is possible and that C-terminal processing of ubiquitin could constitute a biological mechanism, which regulates termination of receptor signaling.

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L-酪氨酸, reagent grade, ≥98% (HPLC)
L-酪氨酸, from non-animal source, meets EP, USP testing specifications, suitable for cell culture, 99.0-101.0%
腺苷 3',5'-环单磷酸 钠盐 一水合物, ≥98.0% (HPLC), powder
腺苷-3′,5′-环单磷酸, ≥98.5% (HPLC), powder
L-酪氨酸, BioUltra, ≥99.0% (NT)
L-酪氨酸, Pharmaceutical Secondary Standard; Certified Reference Material
L-酪氨酸, certified reference material, TraceCERT®, Manufactured by: Sigma-Aldrich Production GmbH, Switzerland
L-酪氨酸, FG