Abstract
The formation of a complex between neuroglobin (Ngb) and cytochrome c (Cyt c) has an important biological role in preventing apoptosis. Binding of Ngb to Cyt c alone is sufficient to block the caspase 9 activation by ferric Cyt c that is released during ischemic insults. Therefore, a detailed information on the Ngb-Cyt c interactions is important for understanding apoptosis. However, the exact nature of the interactions between oxidized human neuroglobin (hNgb) and Cyt c is not well understood. In this work, we used a combination of computational modeling and surface plasmon resonance experiments to obtain and characterize the complex formation between oxidized hNgb and Cyt c. We identified important residues involved in the complex formation, including K72 in Cyt c, which is otherwise known to interact with the apoptotic protease-activation factor-1. Our computational results, together with an optimized structure of the hNgb-Cyt c complex, provide unique insights into how the hNgb-Cyt c complex can abate the apoptotic cascade without an hNgb-Cyt c redox reaction.
Highlights
Neuroglobin (Ngb) is a six-coordinated heme protein that is mainly expressed in nervous and endocrine tissues[1] and the retina[2]
The best predicted human neuroglobin (hNgb)-Cytochrome c (Cyt c) complex structure obtained from docking studies was used in Molecular dynamics (MD) simulations
In this best predicted structure, several interfacial atomic contacts initiated the formation of the complex between hNgb and Cyt c
Summary
Neuroglobin (Ngb) is a six-coordinated heme protein that is mainly expressed in nervous and endocrine tissues[1] and the retina[2]. Since a redox reaction between Ngb and Cyt c is not required to prevent the formation of the apoptosome, the binding of Ngb to Cyt c alone is sufficient to block the Cyt c-induced caspase 9 activation[19] Investigations targeting these two heme proteins in their ferric state are important to the scientific community. Molecular dynamics (MD) simulations are useful in investigations exploring the mechanisms by which the conformational flexibility of a protein is utilized in complex formation and stabilization[26]. While experimental and docking-based computational investigations have been performed, the optimized structure of this important hNgb-Cyt c protein-protein complex has not been established. To the best of our knowledge, this is the first computational investigation of the molecular mechanism underlying the hNgb-Cyt c complex formation, allowing conformational flexibility and structural rearrangements
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