Document Detail

Structural insight for the roles of fas death domain binding to FADD and oligomerization degree of the Fas-FADD complex in the death-inducing signaling complex formation: a computational study.
MedLine Citation:
PMID:  23042204     Owner:  NLM     Status:  MEDLINE    
Fas binding to Fas-associated death domain (FADD) activates FADD-caspase-8 binding to form death-inducing signaling complex (DISC) that triggers apoptosis. The Fas-Fas association exists primarily as dimer in the Fas-FADD complex, and the Fas-FADD tetramer complexes have the tendency to form higher order oligomer. The importance of the oligomerized Fas-FADD complex in DISC formation has been confirmed. This study sought to provide structural insight for the roles of Fas death domain (Fas DD) binding to FADD and the oligomerization of Fas DD-FADD complex in activating FADD-procaspase-8 binding. Results show Fas DD binding to FADD stabilized the FADD conformation, including the increased stability of the critical residues in FADD death effector domain (FADD DED) for FADD-procaspase-8 binding. Fas DD binding to FADD resulted in the decreased degree of both correlated and anticorrelated motion of the residues in FADD and caused the reversed correlated motion between FADD DED and FADD death domain (FADD DD). The exposure of procaspase-8 binding residues in FADD that allows FADD to interact with procaspase-8 was observed with Fas DD binding to FADD. We also observed different degrees of conformational and motion changes of FADD in the Fas DD-FADD complex with different degrees of oligomerization. The increased conformational stability and the decreased degree of correlated motion of the residues in FADD in Fas DD-FADD tetramer complex were observed compared to those in Fas DD-FADD dimer complex. This study provides structural evidence for the roles of Fas DD binding to FADD and the oligomerization degree of Fas DD-FADD complex in DISC formation to signal apoptosis.
Qi Yan; Jay M McDonald; Tong Zhou; Yuhua Song
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-11-05
Journal Detail:
Title:  Proteins     Volume:  81     ISSN:  1097-0134     ISO Abbreviation:  Proteins     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-01-28     Completed Date:  2013-08-02     Revised Date:  2014-03-09    
Medline Journal Info:
Nlm Unique ID:  8700181     Medline TA:  Proteins     Country:  United States    
Other Details:
Languages:  eng     Pagination:  377-85     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Wiley Periodicals, Inc.
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MeSH Terms
Antigens, CD95 / chemistry*
Binding Sites
Caspase 8 / chemistry
Computational Biology / methods*
Fas-Associated Death Domain Protein / chemistry*
Molecular Dynamics Simulation
Multiprotein Complexes / chemistry*
Principal Component Analysis
Protein Binding
Protein Interaction Mapping / methods
Protein Multimerization*
Protein Stability
Protein Structure, Secondary
Signal Transduction*
Static Electricity
Grant Support
5K25CA140791/CA/NCI NIH HHS; K25 CA140791/CA/NCI NIH HHS
Reg. No./Substance:
0/Antigens, CD95; 0/Fas-Associated Death Domain Protein; 0/Multiprotein Complexes; EC 3.4.22.-/Caspase 8

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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