III. Signal transduction and cell cycle | 53. Structure and function of the apoptosome, DISC and PIDDosome complexes

Question 1

I. Basics
1. What are Apoptosome, DISC and PIDDosome?

Answer 1

Apoptosome, DISC and PIDDosome are all complexes that activate initiator caspases (proteases which will induce apoptosis).

Question 2

I. Basics
2. What are the 2 pathway types of mitochondrial apoptosis?

Answer 2

The mitochondrial apoptosis can happen in different pathways: intrinsic or extrinsic

Question 3

I. Basics
3. What does the intrinsic and extrinsic pathways of mitochondrial pathways include?

Answer 3

• The intrinsic pathway includes the release of cytochrome c from mitochondria
• The extrinsic pathway involves binding of extracellular ligand to transmembrane receptors forming DISC.

Question 4

II. Apoptosome
1. Which type of mitochondrial apoptosis pathway that involves apoptosome?

Answer 4

intrinsic apoptotic pathway

Question 5

II. Apoptosome intrinsic apoptotic pathway)
1. What is apoptosome?

Answer 5

A large quaternary protein structure (multiple folded protein subunits in a complex) which is formed in the
process of apoptosis

Question 6

II. Apoptosome intrinsic apoptotic pathway)
2. How is apoptosome formed?

Answer 6

• Its formation is triggered by the release of cytochrome
  c from the mitochondria in response to internal cell
  death stimulus (e.g. DNA damage, viral infection etc.)
• When cytochrome c is released into the cytosol, it will
  bind to an adaptor protein called Apaf1 (apoptotic
  protease activating factor 1)
• Nucleotide dATP (deoxy ATP) will also bind, and the
  structure will undergo oligomerization (process that convers monomers to macromolecular complexes) to form the apoptosome
  => The Apaf1 proteins in the apoptosome will bind to
  pro-caspase 9 proteins
  -> activate initiator caspase 9
  -> will cleave effector caspases 3,6,7
  -> induce apoptosisprocess of apoptosis

Question 7

II. Apoptosome intrinsic apoptotic pathway)
3. What are the consequences if the Apaf1 proteins in the apoptosome will bind to
pro-caspase 9 proteins?

Answer 7

The Apaf1 proteins in the apoptosome will bind to
pro-caspase 9 proteins
=> activate initiator caspase 9
=> will cleave effector caspases 3,6,7
=> induce apoptosisprocess of apoptosis

Question 8

II. Apoptosome intrinsic apoptotic pathway)
4. Give some examples of internal cell
death stimulus?

Answer 8

e.g. DNA damage, viral infection etc.

Question 9

III. PIDDosome
1. What is PIDDosome?

Answer 9

PIDDosome is a multiprotein complex that will active caspase 2 (initiator caspase)

Question 10

III. PIDDosome
2. How is PIDDosome formed?

Answer 10

• Formation of the PIDDosome is triggered by apoptotic signals induced by p53 (tumor suppressor protein), which will activate a protein called PIDD (p53-induced protein with a death domain)
• PIDD will attract an adaptor protein that also contains a death domain, called RAIDD
• RAIDD will recruit procaspase 2 and activate to initiate apoptosis

Question 11

IV. DISC (Death-inducing signaling complex)
1. What type of apoptotic pathway that involves DISC?

Answer 11

extrinsic apoptotic pathway

Question 12

IV. DISC (Death-inducing signaling complex)
2. What is DISC?

Answer 12

Death-inducing signaling complex is a death receptor containing an EC ligand-
binding domain, one single transmembrane domain and an IC death domain

Question 13

IV. DISC (Death-inducing signaling complex)
3. What is the mechanism of DISC?

Answer 13

• When the receptor is activated by the binding of a death ligand (ex: TNFα – tumor necrosis factor), the death domains will bind to 2 adaptor proteins: procaspase-8/10 and FADD (Fas-associated adaptor with death domain)
  -> forms the DISC
• The DISC will bring the procaspases close to each other for auto-activation
  -> form an active initiator caspase dimer (caspase-8/10)
  -> will activate effector caspases to induce apoptosis
• Active caspase-8/10 can also cleave BID to form tBID, which translocates to the
  mitochondria
  -> tBID is needed for cytochrome release = connects the intrinsic and extrinsic pathways

Question 14

IV. DISC (Death-inducing signaling complex)
4. Give an example of a death ligand

Answer 14

TNFα – tumor necrosis factor

Question 15

IV. DISC (Death-inducing signaling complex)
5. When the receptor is activated by the binding of a death ligand (ex: TNFα – tumor necrosis factor), the death domains will bind to 2 adaptor proteins
=> What are they?

Answer 15

procaspase-8/10 and FADD
(Fas-associated adaptor with death domain)

Question 16

V. Further activators of apoptosis
1. What is ER-stress induced apoptosis?

Answer 16

ER-stress induced apoptosis: in response to accumulation of misfolded proteins.

Question 17

V. Further activators of apoptosis
2. What is Granzyme B induced apoptosis?

Answer 17

• Granzyme is a serine protease found in granules of cytotoxic lymphocytes and natural killer cells.
• It is secreted by these cells along with the pore-forming protein perforin to mediate apoptosis in target cells (Effector caspase activation, Bid protein activation).
• Tumor cells may avoid apoptosis by expressing inhibitors for the granzyme B.