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Structural Insight for Roles of DR5 Death Domain Mutations on Oligomerization of DR5 Death Domain–FADD Complex in the Death-Inducing Signaling Complex Formation: A Computational Study

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Abstract

Death receptor 5 (DR5)-induced apoptosis that prioritizes the death of tumor cells has been proposed as one of the promising cancer therapies. In this process, oligomerized DR5 death domain (DD) binding to Fas-associated death domain (FADD) leads to FADD activating caspase-8, which marks the formation of the death-inducing signaling complex (DISC) that initiates apoptosis. DR5 DD mutations found in cancer cells have been suggested to play an important pathological role, the mechanism through which those mutants prevent the DR5-activated DISC formation is not clear yet. This study sought to provide structural and molecular insight for the roles of four selected DR5 DD mutations (E355K, E367K, K415N, and L363F) in the oligomerization of DR5 DD–FADD complex during the DISC formation. Results from the molecular dynamics simulations show that the simulated mutants induce conformational, dynamical motions and interactions changes in the DR5 DD–FADD tetramer complex, including changes in a protein’s backbone flexibility, less exposure of FADD DED’s caspase-8 binding site, reduced H-bonding and hydrophobic contacts at the DR5 DD–FADD DD binding, altered distribution of the electrostatic potentials and correlated motions of residues, and reduced binding affinity of DR5 DD binding to FADD. This study provides structural and molecular insight for the influence of DR5 DD mutations on oligomerization of DR5 DD–FADD complex, which is expected to foster understanding of the DR5 DD mutants’ resistance mechanism against DR5-activated DISC formation.

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Abbreviations

DD:

Death domain

DED:

Death effector domain

DISC:

Death-inducing signaling complex

DR5:

Death receptor 5

FADD:

Fas-associated protein with death domain

TNFR:

Tumor necrosis factor receptor

FasL:

Fas ligand

TRAIL:

TNF-related apoptosis-inducing ligand

MD:

Molecular dynamics

NPT:

Constant number-pressure-temperature

NVT:

Constant number-volume-temperature

DCCM:

Dynamical cross correlation maps

MM-PBSA:

The molecular mechanics/Poisson–Boltzmann surface area

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Acknowledgments

The authors thank Alabama Supercomputer Authority and UAB Cheaha cluster for providing computing time.

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Authors and Affiliations

  1. Department of Biomedical Engineering, The University of Alabama at Birmingham, 803 Shelby Interdisciplinary Biomedical Research Building, 1825 University Boulevard, Birmingham, AL, 35294, USA

    Yuhua Song

  2. Department of Chemistry, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Hongyi Yang

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  1. Hongyi Yang
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Correspondence to Yuhua Song.

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This work was supported in part by an NIH K25 award (5K25CA140791) to Y. H. Song.

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Yang, H., Song, Y. Structural Insight for Roles of DR5 Death Domain Mutations on Oligomerization of DR5 Death Domain–FADD Complex in the Death-Inducing Signaling Complex Formation: A Computational Study. J Mol Model 22, 89 (2016). https://doi.org/10.1007/s00894-016-2941-0

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