Search results for CYCS

Showing 17 results out of 22

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Protein (4 results from a total of 4)

Identifier: R-HSA-53259
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: CYCS: P99999
Identifier: R-HSA-352608
Species: Homo sapiens
Compartment: mitochondrial inner membrane
Primary external reference: UniProt: CYCS: P99999
Identifier: R-HSA-114244
Species: Homo sapiens
Compartment: mitochondrial intermembrane space
Primary external reference: UniProt: P99999
Identifier: R-HSA-5688308
Species: Homo sapiens
Compartment: mitochondrial intermembrane space
Primary external reference: UniProt: CYCS: P99999

DNA Sequence (1 results from a total of 1)

Identifier: R-HSA-2466368
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: ENSEMBL: ENSG00000172115

Reaction (6 results from a total of 11)

Identifier: R-HSA-1592231
Species: Homo sapiens
Compartment: nucleoplasm, cytosol
The gene encoding cytochrome c (CYCS) is transcribed in the nucleus to yield mRNA and the mRNA is translated in the cytosol to yield the precursor of cytochrome c, which is then imported into the mitochodrial matrix and associates with the matrix face of the inner membrane.
Identifier: R-HSA-114254
Species: Homo sapiens
Compartment: cytosol
The apoptotic protease‑activating factor 1 (APAF1) is a cytosolic multidomain adapter protein containing an N‑terminal caspase recruitment domain (CARD), followed by a central nucleotide‑binding & oligomerization domain (NOD, also known as NB‑ARC) and a C‑terminal regulatory region with WD40 repeats which form the 7- and 8-bladed β-propellers (Inohara N and Nunez G 2003; Danot O et al. 2009; Yuan S et al. 2011). Under steady‑state, non‑apoptotic conditions, APAF1 exists as an ADP‑bound, autoinhibited monomer (Riedl SJ et al. 2005; Reubold TF et al. 2009). During apoptosis, cytochrome c (CYCS) is released from the mitochondrial intermembrane space to the cytosol where it binds APAF1 between the two WD40 repeat domains in the C‑terminal regulatory region (Zou et al. 1997; Liu X et al. 1996; Shalaeva DN et al. 2015; Zhou M et al. 2015). CYCS binding causes an upward rotation of the β-propeller region which is accompanied by conformational changes in APAF1 and the replacement of ADP by dATP or ATP triggering APAF1 oligomerization into a heptameric, wheel‑shaped signaling platform (Acehan D et al. 2002; Yu X et al. 2005, Kim HE et al. 2005; Yuan S et al. 2010, 2013; Li P et al. 1997; Jiang X & Wang X 2000; Zhou M et al. 2015). Moreover, the N-terminal CARD in the inactive APAF1 monomer is not shielded from other proteins by β–propellers. Hence, the APAF1 CARD may be free to interact with a procaspase-9 CARD either before or during apoptosome assembly (Yuan S et al. 2013). Physiological concentrations of calcium ion negatively affect the assembly of apoptosome and activation of CASP9 by inhibiting nucleotide exchange in the monomeric, autoinhibited APAF1 (Bao Q et al. 2007).
Identifier: R-HSA-2466370
Species: Homo sapiens
Compartment: nucleoplasm
As inferred from mouse, PGC-1beta (PPARGC1B) binds NRF1 and coactivates genes regulated by NRF1.
Identifier: R-HSA-6804596
Species: Homo sapiens
Compartment: cytosol
The APAF1 interacting protein (APIP) is an endogenous regulators of the apoptosome apparatus. APIP is thought to bind to the CARD domain of APAF1 preventing procaspase-9 recruitment to the apoptosome (Cho DH et al., 2004; Cao G et al., 2004; Kang W et al. 2014). Moreover, during hypoxic conditions, APIP may also induce sustained activation of AKT and ERK1/2 kinases, which directly phosphorylate procaspase-9 to inhibit its activation in the apoptosome (Cho DH et al., 2007).
Identifier: R-HSA-114256
Species: Homo sapiens
Compartment: cytosol
The protease caspase‑9 (CASP9) is normally present as an inactive monomeric propeptide (procaspase‑9 or zymogen). Upon apoptosis procaspase‑9 (CASP9(1‑416) is recruited to APAF1:cytochrome C (CYCS):ATP complex to form the caspase‑activating apoptosome (Hu Q et al. 2014; Cheng TC et al. 2016). The cryo-EM structures have established that the nucleotide-binding oligomerization domain (NOD) of APAF1 mediates the heptameric oligomerization of APAF1, while its tryptophan-aspartic acid (WD40) domain interacts with CYCS (Yuan S & Akey CW 2013). The caspase recruitment domain (CARD) of APAF1 recruits the N‑terminal CARD of CASP9(1‑416) through homotypic CARD:CARD interactions (Li P et al. 1997; Qin H et al. 1999; Yuan S et al. 2010; Yuan S & Akey CW 2013). These homotypic interaction motifs are thought to interact with each other through three types of interfaces, type I, II, and III, which cooperate to generate homo- and hetero-oligomers from relatively small assemblies to open-ended filaments (Ferrao R & Wu H 2012). Structural and mutagenesis studies showed that all type I, II, and III interfaces are involved in the caspase-9 activation by APAF1-mediated helical oligomerization of CARDs (Hu Q et al. 2014; Cheng TC et al. 2016; Su TW et al. 2017; Li Y et al. 2017). Cryo-EM structure of the holo-apoptosome revealed an oligomeric CARD disk above the heptameric apoptosome ring with estimated molecular ratios between 2-5 zymogens per 7 APAF1 molecules (Hu Q et al. 2014; Cheng TC et al. 2016). The structural and biochemical studies showed that APAF1-CARD and CASP9-CARD initially formed a 1:1 complex in solution, which at higher concentrations is further oligomerized into a 3:3 complex. The 3:3 complex was reported as a core arrangement of the 4:3 or 4:4 APAF1-CARD:CASP9-CARD complex in the helical assembly of the CARD disk (Cheng TC et al. 2016; Su TW et al. 2017; Li Y et al. 2017; Dorstyn L et al. 2018). Thus, APAF1:CASP9 (1-416) heterodimers may be recruted to the assembling apoptosome as part of its activation.

The Reactome event describes the apoptosome assembly with the stoichiometry of 4 procaspase-9 zymogens per 7 APAF1 molecules. The formation of 1:1 and other combinations of APAF1:CASP9(1-416) complexes is not shown.

Identifier: R-HSA-9710354
Species: Homo sapiens
Compartment: cytosol, mitochondrial outer membrane
Gasdermin E (GSDME) is cleaved by caspase 3 (CASP3) at D270 in response to apoptotic stimuli (Rogers C et al. 2017; Wang Y et al. 2017). The released N‑terminal fragment of GSDME (1‑270) targets the plasma membrane to drive pyroptosis in GSDME‑expressing cells (Wang Y et al. 2017). In addition, the N‑terminal fragment of mouse GSDME binds to cardiolipin liposomes causing severe leakage (Wang Y et al. 2017). Although cardiolipin is primarily located in the inner mitochondrial membrane, the outer mitochondrial membrane also contains around 10‑20% cardiolipin and cardiolipin translocates in a regulatable manner between the compartments (Liu J et al. 2003; reviewed in Dudek J 2017). Confocal microscopy and biochemical analysis revealed that tagged‑GSDME (1‑270) localized to mitochondria and triggered release of proapoptotic proteins such as cytochrome c (CYCS) upon ectopic expression in human HeLa cells or human embryonic kidney 293T (HEK293T) cells (Rogers C et al. 2019). Endogenous GSDME (1‑270) also localized to the mitochondrial fraction during apoptosis in TNFα plus actinomycin D (TNFα/actD)‑treated human lymphoid CEM‑C7 cells. Apoptotic stimuli‑triggered cleavage of GSDME (1‑270) induced CYCS release and ROS production in CEM‑C7 cells (Rogers C et al. 2019). These data suggest that at physiological levels the N‑terminal fragment of GSDME (1‑270) can permeabilize the mitochondria in response to apoptotic stimuli (Rogers C et al. 2019).

This Reactome event describes the GSDME (1‑275) binding to mitochondrial cardiolipin leading to CYCS release from the mitochondria.

Complex (5 results from a total of 5)

Identifier: R-HSA-2466382
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-114253
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-6804605
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-6804630
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-114318
Species: Homo sapiens
Compartment: cytosol

Pathway (1 results from a total of 1)

Identifier: R-HSA-111458
Species: Homo sapiens
Compartment: cytosol
The apoptosome is a cytoplasmic protein complex of two major components ‑ the adapter protein apoptotic protease activating factor 1 (APAF1) and the protease caspase‑9 (CASP9) which interact with each other through their caspase recruitment domains (CARD) (Qin et al. 1999; Yuan S et al. 2010; Yuan S & Akey CW 2013). The function of the apoptosome is to assemble a multimeric complex between APAF1 and procaspase-9 CARDs to facilitate CASP9 activation (Jiang X and Wang X 2000; Srinivasrula SM et al. 2001; Shiozaki EN et al. 2002). The apoptosome is assembled upon APAF1 interaction with cytochrome c (CYCS), which is released from the mitochondrial intermembrane space during apoptosis (Zou H et al. 1997; Yuan S et al. 2013; Shakeri R et al. 2017). CYCS‑bound APAF1 undergoes ATP-mediated conformational changes and in the presence of CARD of CASP9 oligomerizes into a heptameric complex, which activates procaspase 9 (Zou H et al. 1997; Bratton SB et al. 2010; Acehan D et al. 2002; Yu X et al. 2005; Yuan S et al. 2010; Su TW et al. 2017). In the apoptosome, recruitment of caspase-9 may occur before oligomerization in the CARD disk, which presumably brings the caspase domain into proximity for their dimerization and activation (Su TW et al. 2017; Hu Q et al. 2014; Cheng TC et al. 2016). Once activated, CASP9 activates downstream effector caspases‑3 and ‑7. The activated effector caspases then cleave various cellular proteins.

Different models have been proposed to explain CASP9 activation: the “proximity‑driven dimerization model” and the “induced conformation model”. The first models states that upon binding to heptameric APAF1, monomers of procaspase‑9 are brought into close proximity at a high concentration (Acehan et al. 2002; Renatus et al. 2001). This induces dimerization which is sufficient for CASP9 activation whereas autoprocessing within the apoptosome complex merely stabilizes CASP9 dimer (Boatright KM et al. 2003; Pop C et al. 2006). The “induced conformation model” is based on the observation that CASP9 has a much higher level of catalytic activity when it's bound to the apoptosome. The model suggests that a conformational change occurs at the active site of CASP9 upon binding to APAF1 thus inducing CASP9 homodimerization and stabilizing it in the catalytically active conformation (Shiozaki EN et al. 2002). CASP9 activation may also involve formation of a multimeric CARD:CARD assembly between APAF1 and procaspase‑9 (Hu Q et al. 2014).

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