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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• 作者：Hongyi Yang ; Yuhua Song
• 关键词：DR5 death domain – FADD complex oligomerization ; DR5 death domain mutations ; DISC ; Molecular dynamics simulations
• 刊名：Journal of Molecular Modeling
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：22
• 期：4
• 全文大小：1,529 KB
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• 作者单位：Hongyi Yang (2)
  Yuhua Song (1)
  
  2. Department of Chemistry, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA
  1. Department of Biomedical Engineering, The University of Alabama at Birmingham, 803 Shelby Interdisciplinary Biomedical Research Building, 1825 University Boulevard, Birmingham, AL, 35294, USA
  
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Computer Applications in Chemistry
  Biomedicine
  Molecular Medicine
  Health Informatics and Administration
  Life Sciences
  Computer Application in Life Sciences
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：0948-5023

文摘

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.