TY - JOUR
T1 - In silico evaluation of the downstream effect of mutated glucagon is consistent with higher blood glucose homeostasis in Galliformes and Strigiformes
AU - Mahnam, Karim
AU - Shakhsi-Niaei, Mostafa
AU - Ziaei, Maryam
AU - Sweazea, Karen L.
N1 - Funding Information:
The authors would like to appreciate the use of the computational clusters of the High Performance Computing Center (Shahrekord University, Iran), to complete this work. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - In contrast to mammals, glucagon is reported as a much more potent blood glucose modulator in birds. Interestingly, we have found p.Thr16Ser mutation, a variation in the highly conserved glucagon hormone, in Galliformes as well as Strigiformes. To check the effect of this mutation on the receptor binding of glucagon, we predicted the ancestral glucagon receptor sequence of all available Galliformes and Strigiformes species. Subsequently, we analysed their binding to the mutated and wild type glucagon (ancestral) by molecular dynamics simulation. At first, we made a model of ancestral glucagon receptor and ancestral mutated, and wild type glucagon in the order Galliformes and Strigiformes. Then we performed molecular dynamics for each Galliformes and Strigiformes receptor as well as each glucagon peptide, respectively. The final structures were used for docking simulation of glucagon to their receptors. The results of the docking simulations showed a stronger binding affinity of mutated glucagon to glucagon receptors. Afterward, we obtained blood glucose concentrations of all available Galliformes members, as well as all available members of its only taxonomic neighbour (order Anseriformes) in superorder Galloanserae. Interestingly the p.Thr16Ser mutation could finely cluster these two orders into two groups: higher blood glucose concentration (order Galliformes, 17.64 ± 1.66 mMol/L) and lower blood glucose concentration (order Anseriformes, 11.34 ± 1.11 mMol/L). Strigiformes which carry the mutated glucagon peptide show also high blood glucose concentrations (17.40 ± 1.51 mMol/L). Therefore, the results suggest this mutation, which leads to stronger binding affinity of mutated glucagon to its receptor, may be a driving force for higher blood glucose homeostasis in the related birds.
AB - In contrast to mammals, glucagon is reported as a much more potent blood glucose modulator in birds. Interestingly, we have found p.Thr16Ser mutation, a variation in the highly conserved glucagon hormone, in Galliformes as well as Strigiformes. To check the effect of this mutation on the receptor binding of glucagon, we predicted the ancestral glucagon receptor sequence of all available Galliformes and Strigiformes species. Subsequently, we analysed their binding to the mutated and wild type glucagon (ancestral) by molecular dynamics simulation. At first, we made a model of ancestral glucagon receptor and ancestral mutated, and wild type glucagon in the order Galliformes and Strigiformes. Then we performed molecular dynamics for each Galliformes and Strigiformes receptor as well as each glucagon peptide, respectively. The final structures were used for docking simulation of glucagon to their receptors. The results of the docking simulations showed a stronger binding affinity of mutated glucagon to glucagon receptors. Afterward, we obtained blood glucose concentrations of all available Galliformes members, as well as all available members of its only taxonomic neighbour (order Anseriformes) in superorder Galloanserae. Interestingly the p.Thr16Ser mutation could finely cluster these two orders into two groups: higher blood glucose concentration (order Galliformes, 17.64 ± 1.66 mMol/L) and lower blood glucose concentration (order Anseriformes, 11.34 ± 1.11 mMol/L). Strigiformes which carry the mutated glucagon peptide show also high blood glucose concentrations (17.40 ± 1.51 mMol/L). Therefore, the results suggest this mutation, which leads to stronger binding affinity of mutated glucagon to its receptor, may be a driving force for higher blood glucose homeostasis in the related birds.
KW - Blood Sugar
KW - Conserved
KW - Galloanserae
KW - Molecular dynamics
KW - Mutation, Phylogeny
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U2 - 10.1016/j.ygcen.2021.113925
DO - 10.1016/j.ygcen.2021.113925
M3 - Article
C2 - 34624309
AN - SCOPUS:85116879201
SN - 0016-6480
VL - 314
JO - General and Comparative Endocrinology
JF - General and Comparative Endocrinology
M1 - 113925
ER -