GKA deel 1 college 11

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  • GK 2009 a.a.m.thomas@uu.nl
  • GK 2009 a.a.m.thomas@uu.nl
  • GK 2009 a.a.m.thomas@uu.nl
  • GK 2009 a.a.m.thomas@uu.nl Formation of pore: Cyt c and other intermembrane proteins escape Heterodimerization between pro- and anti-apoptotic family members. Dimerization is achieved when the BH3 domain of one molecule binds into a hydrophobic pocket formed by the BH1, BH2 and BH3 domains of another family member72. Because of structural constraints, both homodimers and heterodimers are asymmetric molecules. Direct regulation of caspases via adaptor molecules, as has been described in C. elegans. Although the CED-4 homologue Apaf-1 is probably not a Bcl-2 family target, other adaptor proteins, such as BAR (ref. 73), the endoplasmic reticulum-localized protein Bap31 (ref. 74) and Aven (ref. 75), have been described in mammals. Interaction with other mitochondrial proteins, such as VDAC and the adenosine nucleotide transporter (ANT), either to generate a pore for cytochrome c exit, or to modulate mitochondrial homeostasis (for example, opening of the PTP). Oligomerization to form a weakly selective ion channeL
  • GK 2009 a.a.m.thomas@uu.nl
  • GKA deel 1 college 11

    1. 2. Apoptosis: controlled cell-suicide GK '09 www.theses.ulaval.ca/2005/23101/ch01.html
    2. 3. Apoptosis: controlled cell-suicide GK '09 www.theses.ulaval.ca/2005/23101/ch01.html
    3. 4. Apoptosis: controlled cell-suicide GK '09 Tumor cell treated with chemotherapy inducing apoptosis www.theses.ulaval.ca/2005/23101/ch01.html
    4. 5. Result of caspase activity Hengartner (2000) Nature 407: 770-776 <ul><li>Apoptosis </li></ul><ul><ul><li>Controls cell death </li></ul></ul><ul><ul><li>Removes abnormal cells </li></ul></ul><ul><li>Actors </li></ul><ul><ul><li>(later: 2. Bcl-family) </li></ul></ul><ul><ul><li>1. Caspases </li></ul></ul><ul><ul><ul><li>C-Asp-ases </li></ul></ul></ul><ul><ul><ul><li>Proteases </li></ul></ul></ul><ul><ul><ul><li>Cleave many substrates </li></ul></ul></ul><ul><ul><ul><ul><li>Once or twice </li></ul></ul></ul></ul><ul><ul><ul><li>Inactivation (ICAD) </li></ul></ul></ul><ul><ul><ul><ul><li>Caspase-activated DNase </li></ul></ul></ul></ul><ul><ul><ul><li>Activation </li></ul></ul></ul><ul><ul><ul><li>Dissociation </li></ul></ul></ul><ul><ul><ul><li>Releasing active component </li></ul></ul></ul>GK '09
    5. 6. Result of caspase activity Hengartner (2000) Nature 407: 770-776 <ul><li>Apoptosis </li></ul><ul><ul><li>Controls cell death </li></ul></ul><ul><ul><li>Removes abnormal cells </li></ul></ul><ul><li>Actors </li></ul><ul><ul><li>(later: 2. Bcl-family) </li></ul></ul><ul><ul><li>1. Caspases </li></ul></ul><ul><ul><ul><li>C-Asp-ases </li></ul></ul></ul><ul><ul><ul><li>Proteases </li></ul></ul></ul><ul><ul><ul><li>Cleave many substrates </li></ul></ul></ul><ul><ul><ul><ul><li>Once or twice </li></ul></ul></ul></ul><ul><ul><ul><li>Inactivation (ICAD) </li></ul></ul></ul><ul><ul><ul><ul><li>Caspase-activated DNase </li></ul></ul></ul></ul><ul><ul><ul><li>Activation </li></ul></ul></ul><ul><ul><ul><li>Dissociation </li></ul></ul></ul><ul><ul><ul><li>Releasing active component </li></ul></ul></ul>GK '09
    6. 7. Result of caspase activity Hengartner (2000) Nature 407: 770-776 <ul><li>Apoptosis </li></ul><ul><ul><li>Controls cell death </li></ul></ul><ul><ul><li>Removes abnormal cells </li></ul></ul><ul><li>Actors </li></ul><ul><ul><li>(later: 2. Bcl-family) </li></ul></ul><ul><ul><li>1. Caspases </li></ul></ul><ul><ul><ul><li>C-Asp-ases </li></ul></ul></ul><ul><ul><ul><li>Proteases </li></ul></ul></ul><ul><ul><ul><li>Cleave many substrates </li></ul></ul></ul><ul><ul><ul><ul><li>Once or twice </li></ul></ul></ul></ul><ul><ul><ul><li>Inactivation (ICAD) </li></ul></ul></ul><ul><ul><ul><ul><li>Caspase-activated DNase </li></ul></ul></ul></ul><ul><ul><ul><li>Activation </li></ul></ul></ul><ul><ul><ul><li>Dissociation </li></ul></ul></ul><ul><ul><ul><li>Releasing active component </li></ul></ul></ul>GK '09
    7. 8. Mechanisms of caspase activation Hengartner Nature 407, 2000 <ul><li>Activation by </li></ul><ul><ul><li>a) Processing </li></ul></ul><ul><ul><li>b) Proximity </li></ul></ul><ul><ul><ul><li>Receptor </li></ul></ul></ul><ul><ul><li>c) Assembly holo-enzyme </li></ul></ul><ul><ul><ul><li>APAF= ap optosis- a ctivating f actor </li></ul></ul></ul><ul><ul><ul><li>“ Apoptosoom” </li></ul></ul></ul><ul><li>Auto-catalytic </li></ul><ul><li>Active form is tetramer of processed proteins </li></ul>GK '09
    8. 9. Mechanisms of caspase activation Hengartner Nature 407, 2000 <ul><li>Activation by </li></ul><ul><ul><li>a) Processing </li></ul></ul><ul><ul><li>b) Proximity </li></ul></ul><ul><ul><ul><li>Receptor </li></ul></ul></ul><ul><ul><li>c) Assembly holo-enzyme </li></ul></ul><ul><ul><ul><li>APAF= ap optosis- a ctivating f actor </li></ul></ul></ul><ul><ul><ul><li>“ Apoptosoom” </li></ul></ul></ul><ul><li>Auto-catalytic </li></ul><ul><li>Active form is tetramer of processed proteins </li></ul>GK '09
    9. 10. Mechanisms of caspase activation Hengartner Nature 407, 2000 <ul><li>Activation by </li></ul><ul><ul><li>a) Processing </li></ul></ul><ul><ul><li>b) Proximity </li></ul></ul><ul><ul><ul><li>Receptor </li></ul></ul></ul><ul><ul><li>c) Assembly holo-enzyme </li></ul></ul><ul><ul><ul><li>APAF= ap optosis- a ctivating f actor </li></ul></ul></ul><ul><ul><ul><li>“ Apoptosoom” </li></ul></ul></ul><ul><li>Auto-catalytic </li></ul><ul><li>Active form is tetramer of processed proteins </li></ul>GK '09
    10. 11. Two major apoptosis pathways Hengartner, Nature 407, 2000 <ul><li>Intrinsic and extrinsic pathways </li></ul><ul><li>Initiator: caspase 8 or 9 </li></ul><ul><li>CD95=Fas </li></ul>GK '09
    11. 12. Activation of an apoptosis receptor Morley and Coldwell, in ‘Translational control in biology and medicine’, 2007 CSHL Press, CSH, New York <ul><li>DD </li></ul><ul><ul><li>death domain </li></ul></ul><ul><li>DED </li></ul><ul><ul><li>Death effector domain </li></ul></ul><ul><li>DISC </li></ul><ul><ul><li>Death-inducing signaling complex </li></ul></ul><ul><li>FADD </li></ul><ul><ul><li>Fas-associated death domain </li></ul></ul>GK '09
    12. 13. Two major apoptosis pathways Hengartner Nature 407, 2000 <ul><li>Initiator: caspase 8 or 9 </li></ul><ul><li>CD95=Fas </li></ul><ul><li>In- and extrinsic activation </li></ul><ul><ul><li>Coupled via Bid! </li></ul></ul><ul><li>IAP: inhibitor of apoptosis </li></ul><ul><li>DIABLO: direct IAP-binding protein with low pI </li></ul><ul><li>SMAC: 2 nd mitochondria-derived activator of A </li></ul><ul><li>Role p53: induction Bax </li></ul>GK '09
    13. 14. Two major apoptosis pathways Hengartner Nature 407, 2000 <ul><li>Initiator: caspase 8 or 9 </li></ul><ul><li>CD95=Fas </li></ul><ul><li>In- and extrinsic activation </li></ul><ul><ul><li>Coupled via Bid! </li></ul></ul><ul><li>IAP: inhibitor of apoptosis </li></ul><ul><li>DIABLO: direct IAP-binding protein with low pI </li></ul><ul><li>SMAC: 2 nd mitochondria-derived activator of A </li></ul><ul><li>Role p53: induction Bax </li></ul>GK '09
    14. 15. Bcl-2 family Hengartner, Nature 407, 2000 <ul><li>2 nd family of actors </li></ul><ul><ul><li>Bcl2-family </li></ul></ul><ul><ul><li>B - c ell l ymphoma- l eukemia </li></ul></ul><ul><ul><li>Heterodimers </li></ul></ul><ul><ul><li>Group 1: anti-apoptotic, group 2: pro-apoptotic </li></ul></ul><ul><ul><li>Mitochondrial transmembrane proteins </li></ul></ul>GK '09
    15. 16. Mechanism of Bcl-members Hengartner, Nature 407, 2000 GK '09 Pore formation Dimerization! (Not a mechanism!) Mediated interaction Ion channel Homeostasis Bcl2 family member
    16. 17. How is cytochrome C released from mitochondrion? Hengartner Nature 407, 2000 <ul><li>Bcl2 looks like diphteria toxin </li></ul><ul><ul><li>Membrane hole </li></ul></ul><ul><li>Recruitment other proteins: pore, channel </li></ul><ul><ul><li>VDAC= voltage-dependent anion channel </li></ul></ul><ul><li>Homeostasis mitochondrion </li></ul><ul><ul><li>Osmolarity: swelling, lysis </li></ul></ul><ul><li>VDAC=subunit of mitochondrial pore </li></ul><ul><ul><li>CytC release </li></ul></ul>GK '09 ================= <ul><li>Cytochome C has two functions </li></ul><ul><ul><li>In apoptose </li></ul></ul><ul><ul><li>As electron carrier in respiratory chain </li></ul></ul>

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