PMID- 26995783 OWN - NLM STAT- MEDLINE DCOM- 20161213 LR - 20181113 IS - 0948-5023 (Electronic) IS - 0948-5023 (Linking) VI - 22 IP - 4 DP - 2016 Apr TI - 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. PG - 89 LID - 10.1007/s00894-016-2941-0 [doi] AB - 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. FAU - Yang, Hongyi AU - Yang H AD - Department of Chemistry, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA. FAU - Song, Yuhua AU - Song Y AD - 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. LA - eng GR - 5K25CA140791/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20160319 PL - Germany TA - J Mol Model JT - Journal of molecular modeling JID - 9806569 RN - 0 (Death Domain Receptor Signaling Adaptor Proteins) RN - 0 (FADD protein, human) RN - 0 (Fas-Associated Death Domain Protein) RN - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand) RN - 0 (TNFRSF10B protein, human) RN - EC 3.4.22.- (CASP8 protein, human) RN - EC 3.4.22.- (Caspase 8) SB - IM MH - Amino Acid Motifs MH - Amino Acid Substitution MH - Binding Sites MH - Caspase 8/*chemistry/genetics MH - Death Domain Receptor Signaling Adaptor Proteins/*chemistry/genetics MH - Fas-Associated Death Domain Protein/*chemistry/genetics MH - Humans MH - Hydrogen Bonding MH - Hydrophobic and Hydrophilic Interactions MH - *Molecular Dynamics Simulation MH - *Mutation MH - Protein Binding MH - Protein Domains MH - Protein Multimerization MH - Protein Structure, Secondary MH - Quantum Theory MH - Receptors, TNF-Related Apoptosis-Inducing Ligand/*chemistry/genetics MH - Static Electricity MH - Thermodynamics MH - User-Computer Interface OTO - NOTNLM OT - DISC OT - DR5 death domain mutations OT - DR5 death domain - FADD complex oligomerization OT - Molecular dynamics simulations EDAT- 2016/03/21 06:00 MHDA- 2016/12/15 06:00 CRDT- 2016/03/21 06:00 PHST- 2015/09/16 00:00 [received] PHST- 2016/02/22 00:00 [accepted] PHST- 2016/03/21 06:00 [entrez] PHST- 2016/03/21 06:00 [pubmed] PHST- 2016/12/15 06:00 [medline] AID - 10.1007/s00894-016-2941-0 [pii] AID - 10.1007/s00894-016-2941-0 [doi] PST - ppublish SO - J Mol Model. 2016 Apr;22(4):89. doi: 10.1007/s00894-016-2941-0. Epub 2016 Mar 19.