Journal
FEBS LETTERS
Volume 589, Issue 19, Pages 2819-2824Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.febslet.2015.07.052
Keywords
Chemokine; Glycosaminoglycan; Protein engineering; Carbohydrate binding protein; Cancer therapy; Tumour metastasis
Funding
- DOC Fellowship of the Austrian Academy of Sciences
- British Heart Foundation [FS/15/19/31327] Funding Source: researchfish
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We have engineered GPCR (G protein-coupled receptor) knock-out and high GAG-binding affinity into CXCL12 alpha to inhibit CXCL12 alpha-induced cell migration. Compared to wtCXCL12, the mutant CXCL12 alpha (Delta 8 L29K V39K) exhibited a 5.6-fold and a 2.2-fold affinity increase for heparin and heparan sulfate, respectively. From NaCl-based heparin displacement chromatography we concluded that more amino acid replacements would lead to altered GAG (glycosaminoglycan) ligand specificity. GAG silencing by this mutant was shown in a murine seeding model of human cancer cells, whereby a greatly reduced number of liver metastases was detected when the animals were treated intravenously with 1 mg/kg CXCL12 alpha (Delta 8 L29K V39K) before cancer cell application. (C) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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