Apoptosome Structure, Assembly, and Procaspase Activation

Department of Physiology and Biophysics, Boston University School of Medicine, 700 Albany Street, Boston, MA 02118, USA.
Structure (Impact Factor: 5.62). 04/2013; 21(4):501-15. DOI: 10.1016/j.str.2013.02.024
Source: PubMed


Apaf-1-like molecules assemble into a ring-like platform known as the apoptosome. This cell death platform then activates procaspases in the intrinsic cell death pathway. In this review, crystal structures of Apaf-1 monomers and CED-4 dimers have been combined with apoptosome structures to provide insights into the assembly of cell death platforms in humans, nematodes, and flies. In humans, the caspase recognition domains (CARDs) of procaspase-9 and Apaf-1 interact with each other to form a CARD-CARD disk, which interacts with the platform to create an asymmetric proteolysis machine. The disk tethers multiple pc-9 catalytic domains to the platform to raise their local concentration, and this leads to zymogen activation. These findings have now set the stage for further studies of this critical activation process on the apoptosome.

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    • "Initiators of this pathway include UV irradiation and cytotoxic drugs. An apoptosome is formed by the interaction of cytochrome c, Apaf-1, d-ATP/ATP and procaspase-9 with subsequent initiation of the caspase cascade [22]. Over-expression of Bcl-2 and associated anti-apoptotic proteins Bcl-xL, Mcl-1, A1/Bf1 and Bcl-w occurs in substantial subsets of common cancer types that include pancreatic , ovarian, lymphoma, multiple myeloma, lung adenocarcinoma, prostate adenocarcinoma and others. "
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    ABSTRACT: Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Seminars in Cancer Biology 03/2015; ePub ahead of print. DOI:10.1016/j.semcancer.2015.03.001 · 9.33 Impact Factor
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    • "The apoptosome has a ring shaped molecular structure that activates enzymes involved in cell death. One of the major units of this structure is the Apaf-1 molecule (Yuan and Akey, 2013). Apaf-1 expression is stimulated by bortezomib in hepatoma cells (Calvaruso et al., 2007). "
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    ABSTRACT: Proteasome inhibitors and melatonin both are intimately involved in the regulation of major signal transduction proteins including p53, cyclin p27, transcription factor NF-kB, apoptotic factors Bax and Bim, caspase 3, caspase 9, anti-apoptotic factor Bcl-2, TRAIL, NRF2 and transcription factor beta-catenin. The fact that these factors are shared targets of the proteasome inhibitor bortezomib and melatonin suggests the working hypothesis that melatonin is a proteasome inhibitor. Supporting this hypothesis is the fact that melatonin shares with bortezomib a selective pro-apoptotic action in cancer cells. Furthermore, both bortezomib and melatonin increase the sensitivity of human glioma cells to TRAIL-induced apoptosis. Direct evidence for melatonin inhibition of the proteasome was recently found in human renal cancer cells We raise the issue whether melatonin should be investigated in combination with proteasome inhibitors to reduce toxicity, to reduce drug resistance, and to enhance efficacy. This may be particularly valid for hematological malignancies in which proteasome inhibitors have been shown to be useful. Further studies are necessary to determine whether the actions of melatonin on cellular signaling pathways are due to a direct inhibitory effect on the catalytic core of the proteasome, due to an inhibitory action on the regulatory particle of the proteasome, or due to an indirect effect of melatonin on phosphorylation of signal transducing factors.
    Life Sciences 09/2014; 115(1-2). DOI:10.1016/j.lfs.2014.08.024 · 2.70 Impact Factor
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    • "In NLRC4, an NLR with a CARD, its LRR domain plays an important role in inhibiting NLR oligomerization (Hu et al., 2013). Due to their domain similarity to Apaf-1-like molecules that form ring-like platforms through the NBDs to induce caspase activation and apoptosis (Yuan and Akey, 2013),the overarching paradigm appears to presume that NLRP inflammasomes are also ring-like structures organized by the NBD. Formation of filamentous structures in the AIM2 PYD /ASC PYD interaction prompted us to examine ASC-dependent NLRP inflammasomes using the prototypical member NLRP3. "
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    ABSTRACT: Inflammasomes elicit host defense inside cells by activating caspase-1 for cytokine maturation and cell death. AIM2 and NLRP3 are representative sensor proteins in two major families of inflammasomes. The adaptor protein ASC bridges the sensor proteins and caspase-1 to form ternary inflammasome complexes, achieved through pyrin domain (PYD) interactions between sensors and ASC and through caspase activation and recruitment domain (CARD) interactions between ASC and caspase-1. We found that PYD and CARD both form filaments. Activated AIM2 and NLRP3 nucleate PYD filaments of ASC, which, in turn, cluster the CARD of ASC. ASC thus nucleates CARD filaments of caspase-1, leading to proximity-induced activation. Endogenous NLRP3 inflammasome is also filamentous. The cryoelectron microscopy structure of ASC(PYD) filament at near-atomic resolution provides a template for homo- and hetero-PYD/PYD associations, as confirmed by structure-guided mutagenesis. We propose that ASC-dependent inflammasomes in both families share a unified assembly mechanism that involves two successive steps of nucleation-induced polymerization. PAPERFLICK:
    Cell 03/2014; 156(6):1193-206. DOI:10.1016/j.cell.2014.02.008 · 32.24 Impact Factor
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