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Characterization of natural posttranslational modifications of CCL2 and CCR2: role in activity regulation and quantification of proteoforms in inflammatory disorders

CCL2 is part of the chemokine family and is crucial for recruiting immune cells by binding to its receptor CCR2. Due to its central role in monocyte recruitment and activation during immune responses and the expression of CCR2 on endothelial cells, the CCL2/CCR2 axis has been implicated in inflammatory disorders and angiogenesis. Although CCL2 was found to be O-glycosylated more than three decades ago, limited information about the functional effects of this modification exists. In addition, the receptor CCR2 carries several predicted glycosylation and tyrosine sulfation sites in its, for chemokine binding, crucial N-terminal domain. We will produce defined O-glycosylated CCL2 proteins and compare these in binding and signaling assays on immune cells and endothelial cells to study the effects of CCR2 ligand and receptor modifications on molecular interactions and biological responses. We will develop methods to quantify expression of individual CCL2 glycoforms in complex samples to evaluate whether O-glycosylation is regulated in a cell-type/tissue specific manner and to detect glycoforms in patient samples such as synovial fluids and bronchoalveolar lavages. We will correlate ligand and receptor modifications with patient pathology and disease intensity. This project will enhance our understanding of the regulation of the activity of the CCL2/CCR2 system in immune responses and regulation of angiogenesis.

Date:1 Jan 2023 →  Today
Keywords:glycosylation, chemokines, G protein-coupled receptor signaling
Disciplines:Cell movement, Cell signalling, Inflammation, Posttranslational modifications, Proteins