Abstract
Chemokines are chemotactic cytokines involved in leucocyte trafficking to infected tissue. Growth-related oncogene (GRO) chemokines namely CXCL1, CXCL2 and CXCL3 are neutrophil activating chemokines sharing a conserved three-dimensional structure, but encompassing functional diversity due to gene duplication and evolutionary events. However, the evolutionary mechanisms including selection pressures involved in diversification of GRO genes have not yet been characterized. Here, we performed comprehensive evolutionary analysis of GRO genes among different mammalian species. Phylogenetic analysis illustrated a species-specific evolution pattern. Selection analysis evidenced that these genes have undergone concerted evolution. Seventeen positively selected sites were obtained, although the majority of the protein is under purifying selection. Interestingly, these positively selected sites are more concentrated on the C-terminal/glycosaminoglycan (GAG) binding and dimerization segment compared to receptor binding domain. Substitution rate analysis confirmed the C-terminal domain of GRO genes as the highest substituted segment. Further, structural analysis established that the nucleotide alterations in the GAG binding domain are the source of surface charge modulation, thus generating the differential GAG binding surfaces and multiple binding sites as per evolutionary pressure, although the helical surface is primordial for GAG binding. Indeed, such variable electrostatic surfaces are crucial to regulate chemokine gradient formation during a host's defence against pathogens and also explain the significance of chemokine promiscuity.
Highlights
Chemokines are small (8–10 kD) signalling entities involved in numerous physiological and pathological events including chemotaxis, inflammation, angiogenesis, haematopoiesis, tumourigenesis etc. [1,2]
A total of 83 gene/amino acid sequences of growth-related oncogene (GRO) chemokines (CXCL1-38, CXCL2-21, CXCL3-24) from different mammalian species were obtained from the sequence databases of GENBANK, Uniprot and Ensemble, for which the unique IDs are listed in electronic supplementary material, table S1
To rejuvenate the historical events that have occurred during the course of evolution of GRO genes, we constructed a phylogenetic tree using the amino acid sequences of GRO proteins
Summary
Chemokines are small (8–10 kD) signalling entities involved in numerous physiological and pathological events including chemotaxis, inflammation, angiogenesis, haematopoiesis, tumourigenesis etc. [1,2]. Humans express around 50 chemokines and are segregated into four different classes (CC, CXC, CX3C, C) based on the position of Nterminal cysteine residues [5]. They share a structurally conserved monomeric fold, comprising a long disordered N-terminal domain followed by a 310 helix, three anti-parallel β-strands and a C-terminal α-helix (figure 1a,b). Chemokines can oligomerize into dimers, tetramers and other higher-order oligomers [6]. They form two types of dimers, namely CC and CXC type dimers. Several other intermolecular contacts for CXC dimer formation include hydrophobic, electrostatic/van der Waals interactions between the α-helices (α–α ) and with β-strand (α–β ) residues (figure 1d,e)
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