tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c

摘要: BID is a member of the BH3-domain-only subgroup BCL-2 family members proposed to connect proximal death and survival signals core apoptotic pathway at level classic that bear multiple Bcl-2 homology (BH) domains (Adams Cory 1998; Gross et al. 1999a). This set pro-apoptotic proteins shares their only sequence within BH3 amphipathic α-helical domain essential for killing activity heterodimerization with other members. Evidence these reside conserved cell was strongly supported by demonstration egl-1, upstream negative regulator anti-apoptotic ced-9 gene in Caenorhabditis elegans, encodes protein (Conradt Horvitz 1998). Several appear exist an inactive conformation viable cells, but undergo post-translational modification response select assume active conformation. These modifications dictate subcellular location binding partners such proteins. For example, BAD factor signaling robustly phosphorylated on serine residues, which inactivates molecule. Phosphorylated does not bind or BCL-XL, sequestered cytosol bound 14-3-3 (Zha 1996). connects pathways activate PI3-K phosphorylate Ser136 (Datta 1997; del Peso 1997), whereas factors mitochondrial-anchored PKA holoenzyme complex result phosphorylation Ser112 site (Harada 1999). BIM, several stimuli, moves from microtubules mitochondria where it appears BCL-XL promote (Puthalakath 1999). BID first noted its capacity either BAX death. Mutational analysis indicated intact required BAX, this correlated ability induce suggested model served as ligand moved mitochondrial membrane inactivate (Wang More recently, has been refined recognition cytosolic p22 activated caspase-8 cleavage following engagement Fas TNFR1 receptors cells (Li Luo 1999b). The truncated p15 (tBID) translocates mitochondria, inserts into outer membrane. Immunodepletion preparations argued tBID release cytochrome c (Luo shown oligomerization c/Apaf-1/Caspase-9 complex, activates caspase−9 downstream effector caspase−3 caspase−7 (Liu 1996; Li Zou 1997). An absence similar deaths Apaf-1 caspase-9-deficient mice lends support position linear developmental apoptosis (Cecconi Hakem Kuida Yoshida 1998). Bid-deficient revealed critical caspase substrate vivo (Yin proved important hepatocytes c, dysfunction even activation vivo. Other types do absolutely require FasL- TNFα-induced still demonstrate lack release, diminished activity, altered pattern Bid−/− mice. Thus, certain BID-dependent amplification loop releases oligomerizing caspase-9 sufficient caspases execute apoptosis. However, precise mechanism whereby released remains uncertain, observations have varied different signals. Following growth withdrawal, swelling noted. In model, defective exchange ADP results hyperpolarization inner membrane, increase matrix volume, nonspecific rupture releasing intermembrane space including (Vander Heiden signals, translocate apparent homo-oligomerized integral (Wolter Recent studies using recombinant pure liposomes indicate form pore utilizing four molecules will transport (Saito 2000). suggest they could more global permeabilization (Basanez 1999; Kluck 1999). Two broad categories mechanisms might account how release. As noted, serve resident receptor c. Alternatively, also conceivable would itself function participating intramembranous To date, one molecule loss-of-function approaches immunodepletion knockout. Moreover, becomes alkali-resistant, translocation mitochondria. Despite limited domain, BID's overall content three-dimensional structure remarkably (Muchmore Chou McDonnell includes presence two central hydrophobic helices constitute potential pore-forming domains, are those bacterial toxins diptheria toxin fragment B colicin. Finally, (Schendel 1999) like BCL-2, (Antonsson Minn Schlesinger 1997) ion-conductive pores vitro artificial lipid bilayers. constellation findings credence hypothesis be effector. Here we study physiologically BID. targeting surface trigger BAK functions membrane-targeted concentrated ligand. induces BAK, knockout importance event cascade integrates irreversible efflux