Computational analysis of ligand-receptor interactions in wild-type and mutant erythropoietin complexes
Received 14 June 2018
Accepted for publication 30 August 2018
Published 15 October 2018 Volume 2018:11 Pages 1—8
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 3
Editor who approved publication: Dr Juan Fernandez-Recio
Nicholas J Pekas, Samuel S Newton
Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA
Background: Erythropoietin (EPO), a pleiotropic cytokine, binds to its receptor (EPOR) in bone marrow, activating a signaling cascade that results in red blood cell proliferation. A recently discovered naturally occurring EPO mutation (R150Q) at active site 1 (AS1) of the protein was shown to attenuate its canonical downstream signaling, eliminating its hematopoietic effects and causing a fatal anemia. The purpose of this work was to analyze the EPO–EPOR complex computationally to provide a structural explanation for this signaling change.
Materials and methods: Computational structural biology analyses and molecular dynamics simulations were used to determine key interaction differences between the R150Q mutant and the wild-type form of EPO. Both were compared to another variant mutated at the same position, R150E, which also lacks hematopoietic activity.
Results: The ligand–receptor interactions of the R150Q and R150E mutants showed significant variations in how they interacted with EPOR at AS1 of the EPO–EPOR complex. Both lost specific reported salt bridges previously associated with full complex activation.
Conclusion: This work describes how the ligand–receptor interactions at AS1 of the EPO–EPOR complex respond to mutations at the 150th position. The interactions at AS1 were used to propose a potential mechanism by which the binding of EPO to the extracellular domain of EPOR influences its cytosolic domain and the resulting signaling cascade.
Keywords: molecular dynamics, signaling cascade, binding affinity, hematopoiesis
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