Death receptors are members of the TNF receptor superfamily that mediate direct caspase activation and apoptotic cell death. The prototypical members of death receptors include Fas and TNFR1, which bind respectively to FasL and TNFalpha. While Fas is an efficient apoptosis inducer, the cellular effects of TNFR1 are characterized by a remarkable duality that features transcriptional gene activation for inflammatory and acute phase responses in addition to cell death induction. A series of intracellular adapter proteins have been found to mediate the initial steps of signal transduction of these receptors. The death domains in the intracellular regions of Fas and TNFR1 recruits respectively FADD and TRADD, which are also death domain-containing proteins. TRADD is a multi-functional protein that can recruit at least three additional proteins, FADD, RIP and TRAF2. The FADD protein is a direct caspase activator for both Fas and TNFR1, while TRAF2 couples TNFR1 to kinase activation and the activation of transcription factors in the NF-kappaB and AP-1 family. The RIP protein, which also contains a death domain, can also activate NF-kappaB. To understand the protein-protein interactions involved in these initial steps of death receptor signaling, we propose a systematic structural study using X-ray crystallography, biophysical techniques, and in vivo cellular methods. The proposed research should shed light on the structural basis for the transduction of signals from receptors to downstream effectors by these proteins.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047831-03
Application #
6511317
Study Section
Biophysical Chemistry Study Section (BBCB)
Program Officer
Winter, David B
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
3
Fiscal Year
2002
Total Cost
$296,625
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065