Computational analysis of ligand-receptor interactions in wild-type and mutant erythropoietin complexes.
Adv Appl Bioinform Chem
; 11: 1-8, 2018.
Article
em En
| MEDLINE
| ID: mdl-30410371
ABSTRACT
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 ANDMETHODS:
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
Adv Appl Bioinform Chem
Ano de publicação:
2018
Tipo de documento:
Article