Apoptosis Lecture Notes PDF

dddd https://www.ncbi.nlm.nih.gov/books/ NBK26873/ Lecture BIOL2020 Apoptosis is a distinctive and important mode of “programmed” cell death The Nobel Prize in Physiology or Medicine 2002 c.elegans Sydney Brenner Robert Horvitz "for their discoveries concerning genetic regulation of organ d...

dddd https://www.ncbi.nlm.nih.gov/books/ NBK26873/ Lecture BIOL2020 Apoptosis is a distinctive and important mode of “programmed” cell death The Nobel Prize in Physiology or Medicine 2002 c.elegans Sydney Brenner Robert Horvitz "for their discoveries concerning genetic regulation of organ development and programmed cell death'." John E. Sulston To see a dying cells ● ● ● The lineage of all cells in C.elegans is known Follow them in-vivo They saw cells “dying” They isolated mutants in which the cells remain They reconstructed the apoptotic pathway in worms Sculpting the digits in the developing mouse paw by apoptosis Apoptosis is required to clear the connecting tissue and make arthropod joints Normal https://www.nature.com/articles/ncb0107-17 Without apoptosis Apoptotic cells have intact plasma membranes. Necrotic cells spill their contents into their neighbors Apoptotic cells dies neatly, without damaging its neighbors. Necrosis Apoptosis Apoptosis depends on a proteolytic cascade mediated by Cysteine Aspartate Proteases = Caspases ● ● ● Once activated they chop up strategic proteins in the cell. they are cysteine proteases that use the sulfur atom in cysteine to perform the cleavage reaction. they cut proteins next to aspartate amino acids Caspase-9 is an initiator caspase caspase 3 is an effector caspase Initiator caspases begin the apoptotic program by activating the executioner caspases, which orchestrate the apoptosis program. Caspase 8 and 9 are initiator caspases Caspase 3, 6, and 7 are effector caspases Caspases are synthesized as procaspases and are activated by cleavage large subunit ● ● Caspases are synthesized in the cell as inactive precursors, or procaspases, activated by cleavage at aspartic acids by other caspases small subunit Initiator caspases are inactive monomers that activate when they dimerize and self cleave ● A apoptotic signal triggers the assembly of an adaptor-protein complex Executioner caspases are cleaved and activated by initiator caspases executioner caspases have shorter prodomains Cascade of caspase activations make apoptosis amplifying and irreversible A caspase activated DNAse (CAD) catalyzes the hydrolytic cleavage of DNA Caspase release the brake on DNAses to degrade DNA ← Caspase-activated deoxyribonuclease (DNAse). ← Caspase cleavage site ← Regulatory subunits Our cells use two main activation pathways: one is signaled from outside the cell and is called the extrinsic pathway, and the other is signaled from mitochondria inside the cell and is called the intrinsic pathway Fas ligand killer cell cytochrome c extrinsic pathway intrinsic pathway Activation of cell-surface death receptors initiates the extrinsic pathway activated Fas receptors cluster and expose death domains on the receptor tails, which then bind and cluster a small intracellular adaptor protein called FADD. FADD clusters recruit multiple copies of inactive initiator caspases, which oligomerize. The large structure is called the death-inducing signaling complex (DISC) Cells can also activate their apoptosis program from inside the cell, often in response to developmental signals or to injury such as DNA damage. Fas ligand killer cell cytochrome c extrinsic pathway intrinsic pathway The release of cytochrome c from the mitochondria into the cytoplasm is the signal that activates the intrinsic pathway activation The binding of cytochrome c to Apaf1 exposes an oligomerization domain and a caspase recruitment domain CARD = caspase recruitment domain The oligomerized Apaf1 recruits an inactive caspase-9 monomer, forming the apoptosome. Then, the caspase-9 monomers are activated by dimerization. Apaf1 activates caspases by oligomerizing into a huge complex called the apoptosome cytochrome c ● Apaf1 = apoptotic protease activating factor 1 inactive Apaf-1 → Another line of defense against inappropriate caspase activation is provided by caspase inhibitor proteins called inhibitors of apoptosis (IAPs). ● IAPs bind and prevent activation of some procaspases Bcl2 proteins are the main regulators of the Intrinsic Pathway apoptosis Pro-apoptotic Bcl2 proteins make holes into the mitochondrial membrane Anti-apoptotic Bcl2 proteins inactivate the pro-apoptotic Bcl2 Bcl2 proteins are the main regulators of the Intrinsic Pathway Pro-apoptotic Bcl2 proteins make holes into the mitochondrial membrane Anti-apoptotic Bcl2 proteins inactivate the pro-apoptotic Bcl2 Healthy Neighbors Phagocytose and Digest Apoptotic Cells normal cancer ● Cell competition is a fitness control mechanism in which less fit cells are eliminated from a tissue Caspases degrade a flippase that keeps Phosphatidyl serine inside the cell ● ● In apoptotic cells PtdSer is outside Normal cells recognize apoptotic cells because they have PtdSer outside Ferroptosis is an intracellular iron-dependent form of cell death that is distinct from apoptosis, necrosis Ferroptosis is characterized by the accumulation of oxidatively damaged phospholipids (lipid peroxidation) Summary Cysteine Aspartate Proteases = Caspases ● Initiator caspases are inactive monomers that activate when dimerize ● Caspase-9 is an initiator caspase ● caspase 3 is an effector caspase c.elegans Activation of apoptosis from inside the cell - Intrinsic ● mitochondria ● cytochrome-c ● Apaf1 ● apoptosome Extrinsic pathway Fas ligand and receptor