LEDGF/p75 interacts with divergent lentiviral integrases and ...
Caspases in p75-mediated Neuronal Death Pathway. Cell Death Necrosis –Response to disease...
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Transcript of Caspases in p75-mediated Neuronal Death Pathway. Cell Death Necrosis –Response to disease...
Cell Death
• Necrosis– Response to disease– Inflammatory Response
• Apoptosis– Present in Developing Tissue– Absence of Inflammatory Response– Mediated by certain pathways
Details of the p75-mediated Cell Death Pathway
• NGF• p75 Receptor• Mitochondria (Cytochrome C, Adaptor
Protein-Apaf1, & Smac/Diablo)• MIAP3• Caspase 9• Caspase 6• Caspase 3
N
G
F
Neuronal Death
NGF binds to the p75 receptor. This death receptor initiates the mitochondrial pathway for cell death.
MembraneMembrane
p75
N
G
F
Neuronal Death
The binding then causes the blocking of certain mitochondrial molecules such as BCL-2. This then allows cytochrome C to leave the mitochondrion.
Cyt C
Cyt C
Cyt CCyt C
Cyt C
Cyt C
N
G
F
Neuronal Death
Cytochrome C and apaf1, an adaptor protein, bind and activate caspase 9.
Cyt C
Apaf 1
C9
N
G
F
Neuronal Death
At the same time that Cytochrome C is being released, the mitochondrion also releases Smac/Diablo. S/D blocks MIAP.
C9
Cyt C Apaf 1
Smac/Diablo
MIAP
N
G
F
Neuronal Death
Caspase 9 activation leads to the activation of caspase 6 and 3.
C9Cyt C Apaf 1
Smac/Diablo
MIAP
C6
C3
N
G
F
Neuronal Death
Activation of Caspase 3 and Caspase 6 leads to neuronal death.
C9Cyt C Apaf 1
Smac/Diablo
MIAP
C6
C3
How did we simplify the pathway for a math model?
• Group cellular events together– Caspases 9 and 6
• Eliminate upstream regulatory proteins– Cyt C, Apaf 1, Smac/Diablo
N
G
F
Neuronal Death
MIAP
C6
C3
1. p75 bound and there is no excitation between C3 and C6. What are the conditions for the cell to live?
2. p75 bound and there is excitation between C3 and C6. What are the conditions for the cell to die?
First Model: Vary Connection Between C6 and C3
N
G
F
Neuronal Death
MIAP
C6
C3
1. p75 bound the connection between p75 and C6 is absent. What are the conditions for the cell to live?
2. p75 bound the connection between p75 and C6 is present. What are the conditions for the cell to die?
Second Model: No Excitation Present Between C6 and C3 – Vary connection
between p75 and C6