Abstract
As the linker between the A chain and B chain of proinsulin, C-peptide displays high variability in length and amino acid composition, and has been considered as an inert byproduct of insulin synthesis and processing for many years. Recent studies have suggested that C-peptide can act as a bioactive hormone, exerting various biological effects on the pathophysiology and treatment of diabetes. In this study, we analyzed the coevolution of insulin molecules among vertebrates, aiming at exploring the evolutionary characteristics of insulin molecule, especially the C-peptide. We also calculated the correlations of evolutionary rates between the insulin and the insulin receptor (IR) sequences as well as the domain-domain pairs of the ligand and receptor by the mirrortree method. The results revealed distinctive features of C-peptide in insulin intramolecular coevolution and correlated residue substitutions, which partly supported the idea that C-peptide can act as a bioactive hormone, with significant sequence features, as well as a linker assisting the formation of mature insulin during synthesis. Interestingly, the evolution of C-peptide exerted the highest correlation with that of the insulin receptor and its ligand binding domain (LBD), implying a potential relationship with the insulin signaling pathway.
Highlights
Insulin is a well-studied neuroendocrine peptide involved in metabolism, growth and survival in a wide range of mammalian tissues
The differences in molecules characteristics among the parts of the preproinsulin molecule may result in the diversity of coevolutionary and covariant features
This can be supported by the fact that the A chain sequence exerts moderate conservation compared with the B chain and C-peptide and it shows the medium number of correlated sites of residue substitutions
Summary
Insulin is a well-studied neuroendocrine peptide involved in metabolism, growth and survival in a wide range of mammalian tissues. The insulin sequence can be structurally divided into four parts including the signal peptide, B-chain, C-peptide and A-chain (Figure 1). The amino acid sequences of the A chain and B chain are highly conserved among vertebrates [2]. The main role of insulin is to stimulate glucose uptake into cells by inducing the translocation of the glucose transporter GLUT4 from intracellular storage to the plasma membrane [3,4]. It functions in glycogen synthesis, DNA replication, fatty acid and protein synthesis and modifications of the activities of numerous enzymes [5]
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