title: The role of insulin C-peptide in the coevolution analyses of the insulin signaling pathway: a hint for its functions.
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.
authors.affiliation: State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Zoonoses of CAAS, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Yadong
authors.initials: Y
authors.lastname: Zheng
authors.forename: Junling
authors.initials: J
authors.lastname: Hou
authors.forename: Yongxi
authors.initials: Y
authors.lastname: Dou
authors.forename: Shaohua
authors.initials: S
authors.lastname: Zhang
authors.forename: Xuenong
authors.initials: X
authors.lastname: Luo
authors.forename: Xuepeng
authors.initials: X
authors.lastname: Cai
mesh_terms: D000818:Animals; D002096:C-Peptide / Q000737:chemistry* / Q000235:genetics; D016000:Cluster Analysis; D019143:Evolution, Molecular; D006801:Humans; D007328:Insulin / Q000737:chemistry* / Q000235:genetics; D008957:Models, Genetic; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D011972:Receptor, Insulin / Q000737:chemistry / Q000235:genetics; D020539:Sequence Analysis, Protein; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: D002096:C-Peptide; D007328:Insulin; D011972:Receptor, Insulin