title: 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.
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.
authors.affiliation: Department of Chemistry, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
authors.forename: Hongyi
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Biomedical Engineering, The University of Alabama at Birmingham, 803 Shelby Interdisciplinary Biomedical Research Building, 1825 University Boulevard, Birmingham, AL, 35294, USA. yhsong@uab.edu.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Song
mesh_terms: D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D001665:Binding Sites; D053181:Caspase 8 / Q000737:chemistry* / Q000235:genetics; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000737:chemistry* / Q000235:genetics; D053200:Fas-Associated Death Domain Protein / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding; D000072417:Protein Domains; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D011789:Quantum Theory; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry* / Q000235:genetics; D055672:Static Electricity; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D053418:Death Domain Receptor Signaling Adaptor Proteins; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505530:CASP8 protein, human; D053181:Caspase 8
keywords: DISC; DR5 death domain mutations; DR5 death domain – FADD complex oligomerization; Molecular dynamics simulations