The conformation of the extracellular binding domain of Death Receptor 5 in the presence and absence of the activating ligand TRAIL: A molecular dynamics study

Wassenaar, Tsjerk A., Quax, Wim J. and Mark, Alan E. (2008) The conformation of the extracellular binding domain of Death Receptor 5 in the presence and absence of the activating ligand TRAIL: A molecular dynamics study. Proteins: Structure, Function, and Bioinformatics, 70 2: 333-343. doi:10.1002/prot.21541


Author Wassenaar, Tsjerk A.
Quax, Wim J.
Mark, Alan E.
Title The conformation of the extracellular binding domain of Death Receptor 5 in the presence and absence of the activating ligand TRAIL: A molecular dynamics study
Journal name Proteins: Structure, Function, and Bioinformatics   Check publisher's open access policy
ISSN 1097-0134
Publication date 2008-02-02
Sub-type Article (original research)
DOI 10.1002/prot.21541
Volume 70
Issue 2
Start page 333
End page 343
Total pages 11
Place of publication United States of America
Publisher John Wiley & Sons Inc
Language eng
Subject C1
730108 Cancer and related disorders
250303 Physical Organic Chemistry
Abstract The Death Receptor 5 (DR5), a member of tumor necrosis factor receptor (TNFR) superfamily of receptors, triggers apoptosis (programmed cell death) when stimulated by its tridentate ligand TRAIL. Until recently it was generally assumed that the activation of DR5 resulted from the recruitment of three independent receptor units, leading to the trimerization of intracellular domains. However, there is mounting evidence to suggest that, in the absence of ligand, such cytokine receptors primarily reside as preformed complexes. In this work, molecular dynamics simulations of the TRAIL-DR5 complex, the unbound receptor trimer and individual receptor monomers are compared to gain insight in the mechanism of activation. The results suggest that, in the absence of TRAIL, DR5 has a strong propensity to self-associate and that this is primarily mediated through interactions of the membrane proximal domains. The association of the free receptors leads to a loss of the threefold symmetry found within the receptor-ligand complex. The simulations suggest that the primary role of TRAIL is to induce threefold-symmetry within the DR5 complex and to constrain the receptor to a specific conformation. The implications of this in terms of the mechanism by which the receptor switches from an inactive to an active state are discussed.
Keyword TNF receptor superfamily
cytokine
self-association
pre-ligand association domain
PLAD
molecular dynamics
simulation
Q-Index Code C1
Q-Index Status Confirmed Code

 
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Created: Tue, 13 May 2008, 22:56:38 EST by Darryl Greensill on behalf of School of Chemistry & Molecular Biosciences