PMID- 27720987
OWN - NLM
STAT- MEDLINE
DCOM- 20170619
LR  - 20181113
IS  - 1089-8638 (Electronic)
IS  - 0022-2836 (Print)
IS  - 0022-2836 (Linking)
VI  - 428
IP  - 24 Pt A
DP  - 2016 Dec 4
TI  - Death Receptor 5 Networks Require Membrane Cholesterol for Proper Structure and 
      Function.
PG  - 4843-4855
LID - S0022-2836(16)30416-8 [pii]
LID - 10.1016/j.jmb.2016.10.001 [doi]
AB  - Death receptor 5 (DR5) is an apoptosis-inducing member of the tumor necrosis 
      factor receptor superfamily, whose activity has been linked to membrane 
      cholesterol content. Upon ligand binding, DR5 forms large clusters within the 
      plasma membrane that have often been assumed to be manifestations of receptor 
      co-localization in cholesterol-rich membrane domains. However, we have recently 
      shown that DR5 clusters are more than just randomly aggregated receptors. 
      Instead, these are highly structured networks held together by receptor dimers. 
      These dimers are stabilized by specific transmembrane helix-helix interactions, 
      including a disulfide bond in the long isoform of the receptor. The complex 
      relationships among DR5 network formation, transmembrane helix dimerization, 
      membrane cholesterol, and receptor activity has not been established. It is 
      unknown whether the membrane itself plays an active role in driving DR5 
      transmembrane helix interactions or in the formation of the networks. We show 
      that cholesterol depletion in cells does not inhibit the formation of DR5 
      networks. However, the networks that form in cholesterol-depleted cells fail to 
      induce caspase cleavage. These results suggest a potential structural difference 
      between active and inactive networks. As evidence, we show that cholesterol is 
      necessary for the covalent dimerization of DR5 transmembrane domains. Molecular 
      simulations and experiments in synthetic vesicles on the DR5 transmembrane dimer 
      suggest that dimerization is facilitated by increased helicity in a thicker 
      bilayer.
CI  - Copyright A(c) 2016. Published by Elsevier Ltd.
FAU - Lewis, Andrew K
AU  - Lewis AK
AD  - Department of Biomedical Engineering, University of Minnesota, Twin Cities, 
      Minneapolis, MN 55455, USA.
FAU - Valley, Christopher C
AU  - Valley CC
AD  - Department of Biomedical Engineering, University of Minnesota, Twin Cities, 
      Minneapolis, MN 55455, USA.
FAU - Peery, Stephen L
AU  - Peery SL
AD  - Department of Biomedical Engineering, University of Minnesota, Twin Cities, 
      Minneapolis, MN 55455, USA.
FAU - Brummel, Benjamin
AU  - Brummel B
AD  - Department of Biomedical Engineering, University of Minnesota, Twin Cities, 
      Minneapolis, MN 55455, USA.
FAU - Braun, Anthony R
AU  - Braun AR
AD  - Department of Biomedical Engineering, University of Minnesota, Twin Cities, 
      Minneapolis, MN 55455, USA.
FAU - Karim, Christine B
AU  - Karim CB
AD  - Department of Biochemistry, Molecular Biology, and Biophysics, University of 
      Minnesota, Twin Cities, Minneapolis, MN 55455, USA.
FAU - Sachs, Jonathan N
AU  - Sachs JN
AD  - Department of Biomedical Engineering, University of Minnesota, Twin Cities, 
      Minneapolis, MN 55455, USA. Electronic address: jnsachs@umn.edu.
LA  - eng
GR  - R01 GM107175/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20161006
PL  - Netherlands
TA  - J Mol Biol
JT  - Journal of molecular biology
JID - 2985088R
RN  - 0 (Membrane Lipids)
RN  - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - Caspases/metabolism
MH  - Cholesterol/*metabolism
MH  - Humans
MH  - Jurkat Cells
MH  - Membrane Lipids/*metabolism
MH  - Models, Biological
MH  - Protein Conformation
MH  - *Protein Multimerization
MH  - Proteolysis
MH  - Receptors, TNF-Related Apoptosis-Inducing Ligand/*chemistry/*metabolism
PMC - PMC5394796
MID - NIHMS851023
OTO - NOTNLM
OT  - cholesterol-rich membrane domains
OT  - disulfide bond
OT  - ligand/receptor clustering
OT  - replica exchange molecular dynamics
OT  - transmembrane domain
EDAT- 2016/10/11 06:00
MHDA- 2017/06/20 06:00
PMCR- 2017/04/18
CRDT- 2016/10/11 06:00
PHST- 2016/01/18 00:00 [received]
PHST- 2016/09/16 00:00 [revised]
PHST- 2016/10/02 00:00 [accepted]
PHST- 2016/10/11 06:00 [pubmed]
PHST- 2017/06/20 06:00 [medline]
PHST- 2016/10/11 06:00 [entrez]
PHST- 2017/04/18 00:00 [pmc-release]
AID - S0022-2836(16)30416-8 [pii]
AID - 10.1016/j.jmb.2016.10.001 [doi]
PST - ppublish
SO  - J Mol Biol. 2016 Dec 4;428(24 Pt A):4843-4855. doi: 10.1016/j.jmb.2016.10.001. 
      Epub 2016 Oct 6.