Designing an improved T-cell mobilising CXCL10 mutant through enhanced GAG binding affinity
| Autor: | Sophie Winkler, Andreas J. Kungl, Martha Gschwandtner, Tanja Gerlza, Michael Nagele |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Leukocyte migration Chemokine Protein Conformation T-Lymphocytes T cell Mutant Mutation Missense Bioengineering Molecular Dynamics Simulation Protein Engineering Binding Competitive Biochemistry 03 medical and health sciences 0302 clinical medicine Cell Movement medicine Humans CXCL10 Amino Acid Sequence Molecular Biology Cells Cultured Glycosaminoglycans biology Chemistry Wild type Chemotaxis Cell migration Cell biology Chemokine CXCL10 Chemotaxis Leukocyte 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis biology.protein Protein Binding Biotechnology |
| Zdroj: | Protein Engineering, Design and Selection. 32:367-373 |
| ISSN: | 1741-0134 1741-0126 |
| DOI: | 10.1093/protein/gzz043 |
| Popis: | The chemokine CXCL10 is released by a plethora of cells, including immune and metastatic cancer cells, following stimulation with interferon-gamma. It acts via its GPC receptor on T-cells attracting them to various target tissues. Glycosaminoglycans (GAGs) are regarded as co-receptors of chemokines, which enable the establishment of a chemotactic gradient for target cell migration. We have engineered human CXCL10 towards improved T-cell mobilisation by implementing a single site-directed mutation N20K into the protein, which leads to a higher GAG binding affinity compared to the wild type. Interestingly, this mutation not only increased T-cell migration in a transendothelial migration assay, the mutant intensified T-cell chemotaxis also in a Boyden chamber set-up thereby indicating a strong role of T-cell-localised GAGs on leukocyte migration. A CXCL10 mutant with increased GAG-binding affinity could therefore potentially serve as a T-cell mobiliser in pathological conditions where the immune surveillance of the target tissue is impaired, as is the case for most solid tumors. |
| Databáze: | OpenAIRE |
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