Several mutational changes to proteins involved in apoptosis are listed below. F

Question

Several mutational changes to proteins involved in apoptosis are listed below.
For each, indicate whether you expect it to have a dominant-negative phenotype.
In other words, do you expect it to cause a defect in apoptosis even in cells that
also contain the normal protein? Explain your answer.
A. Deletion of death domain of Fas death receptor.
B. Mutational change to Fas ligand that prevents its oligomerization.
C. Deletion of the death effector domain of FADD.
D. Deletion of the death effector domain of procaspase-8.
E. Deletion of the CARD domain of Apaf-1.
F. Mutation of the catalytic cysteine of caspase-8 to serine.
G. Mutational change to Bax that prevents its oligomerization with itself and
with Bak.
H. Mutational change to IAP that increases its affinity for caspases.

Explanation / Answer

The change in the following genes will lead to the following result with respect to apoptosis.

A. Deletion of death domain of Fas death receptor - inhibits apoptosis.                                                   -- FAS death receptor on the surface of cells that leads to programmed cell death. Deletion of it will effect the apoptosis.

B. Mutational change to Fas ligand that prevents its oligomerization - inhibits apoptosis.                       --FAS ligand is an transmembrane protein and by binding to its receptor initiates apoptosis. If mutation occurs with it, the process can alter.

C. Deletion of the death effector domain of FADD.-  inhibits apoptosis.                                                 -- FAS associating Death Domain (FADD) plays rolein apoptosis cascade. If it is deleted it surely affects the process.

D. Deletion of the death effector domain of procaspase-8-   inhibits apoptosis.                                       -- Death effector Domain is a protien associated with the procaspases and regulates caspase activation.  FADD recruits procaspase 8 and procaspase 10 into a death induced signaling complex. If this is deleted it will not signal the apoptosis and the death of the cells is inhibited.  

E. Deletion of the CARD domain of Apaf-1 -inhibits apoptosis.                                                                -- Apaf 1 is the apoptotic activating factor that involved in the apoptosis.  This protein contains (from the N terminal) a caspase recruitment domain(CARD) and ATPase domain. If deletion of this domain occurs it will disrupt the entire pathway of the caspase activity. In general this bind to the caspase 9.

F. Mutation of the catalytic cysteine of caspase-8 to serine - inhibits apoptosis.                                      --caspases plays a central role in the execution-phase of cell apoptosis. They have cysteine and aspartic acids in their active sites. When the cysteine is replaced by the serine it will change the structural confirmation of the caspase and inhibits the process.

G. Mutational change to Bax that prevents its oligomerization with itself and
with Bak - inhibits apoptosis.                                                                                                               --Because Bak is a proapoptotic member of Bcl-2 gene family which involved in initiation of apoptosis. The Bax protein belongs to the Bcl-2 family and it also involves in apoptosis.

H. Mutational change to IAP that increases its affinity for caspases - inhibits apoptosis. -- IAP are the Inhibitors of the Apoptosis. If mutational change occurs and increases the afffinity towards the caspases then the inhibition of process will occur.

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