Molecular Insights Into The Differential Structure-Dynamics-Stability Features Of Interleukin-8 Orthologs: Implications To Functional Specificity
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES(2020)
摘要
Chemokines are a sub-group of chemotactic cytokines that regulate the leukocyte migration by binding to G-protein coupled receptors (GPCRs) and cell surface glycosaminoglycans (GAGs). Interleukin-8 (CXCL8/IL8) is one of the most essential CXC chemokine that has been reported to be involved in various pathophysiological conditions. Structure-function relationships of human IL8 have been studied extensively. However, no such detailed information is available on IL8 orthologs, although they exhibit significant functional divergence. In order to unravel the differential structure-dynamics-stability-function relationship of IL8 orthologs, comparative molecular analysis was performed on canine (laurasians) and human (primates) IL8 proteins using in-silico molecular evolutionary analysis and solution NMR spectroscopy methods. The residue level NMR studies suggested that, although the overall structural architecture of canine IL8 is similar to that of human IL8, systematic differences were observed in their backbone dynamics and low-energy excited states due to amino acid substitutions. Further, these substitutions also resulted in attenuation of stability and heparin binding affinity in the canine IL8 as compared to its human counterpart. Indeed, structural and sequence analysis evidenced for specificity of molecular interactions with cognate receptor (CXCR1) and glycosaminoglycan (heparin), thus providing evidence for a noticeable functional specificity and divergence between the two IL8 orthologs. (C) 2020 Elsevier B.V. All rights reserved.
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关键词
Chemokines, Interleukin-8, G-protein coupled receptor (GPCR), Glycosaminoglycans (GAGs), Nuclear magnetic resonance (NMR), Molecular evolution, Functional divergence
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