Involved in the activation cascade of caspases responsible for apoptosis execution. Cleaves poly(ADP-ribose) polymerase in vitro, as well as lamins. Overexpression promotes programmed cell death.
Catalysis of the hydrolysis of peptide bonds in a polypeptide chain by a mechanism in which the sulfhydryl group of a cysteine residue at the active center acts as a nucleophile.
We have developed a PCR approach to clone new apoptotic Ced-3/Ice-like cysteine protease genes. This approach uses degenerate oligonucleotides encoding the highly conserved pentapeptides QACRG and GSWFI that are present in all known apoptotic cysteine proteases. Using this approach, we have cloned a novel apoptotic gene from human Jurkat T lymphocytes. The new gene encodes a approximately 34-kilodalton protein that is highly homologous to human CPP32, Caenorhabditis elegans cell death protein CED-3, mammalian Ich-1 (Nedd2), and mammalian interleukin-1 beta converting enzyme. Because of its high homology to the C. elegans Ced-3 gene, we named the new gene mammalian Ced-3 homologue Mch2. Two Mch2 transcripts (Mch2 alpha, 1.7 kb; Mch2 beta, 1.4 kb) were detected in Jurkat T lymphocytes and other cell lines. We believe that the Mch2 alpha transcript encodes the full-length Mch2, whereas the Mch2 beta transcript encodes a shorter Mch2 isoform, probably as a result of alternative splicing. Like interleukin-1 beta converting enzyme and CPP32, recombinant Mch2 alpha, but not Mch2 beta, possesses protease activity, as determined by its ability to cleave the fluorogenic peptide DEVD-AMC. CPP32 and Mch2 alpha can also cleave poly(ADP-ribose) polymerase in vitro, suggesting that these enzymes participate in poly(ADP-ribose) polymerase cleavage observed during cellular apoptosis. In addition, overexpression of recombinant Mch2 alpha, but not Mch2 beta, induces apoptosis in Sf9 insect cells. Our data suggest that Mch2 is a Ced-3/interleukin-1 beta converting enzyme-like cysteine protease and could be another important mediator of apoptosis in mammalian cells.
Interacting selectively and non-covalently with any protein or protein complex (a complex of two or more proteins that may include other nonprotein molecules).
Evidence
1:
Inferred from Physical InteractionIntAct
SATB1 (special AT-rich sequence-binding protein-1) provides a key link between DNA loop organization, chromatin modification/remodeling, and association of transcription factors at matrix attachment regions (MARs). To investigate the role of SATB1 in cellular events, we performed a yeast two-hybrid screen that identified SUMO-1, Ubc9, and protein inhibitor of activated STAT (PIAS) family members as SATB1 interaction partners. These proteins, working in concert, enhanced SUMO conjugation to lysine-744 of SATB1. Overexpression of SUMO or PIAS in Jurkat cells, which express high levels of endogenous SATB1, exhibited enhanced caspase cleavage of this MAR-associating protein. Sumoylation-deficient SATB1 (SATB1(K744R)) failed to display the characteristic caspase cleavage pattern; however, fusion of SUMO in-frame to SATB1(K744R) restored cleavage. A SUMO-independent interaction of inactive caspase-6 and SATB1 was noted. A subset of total cellular SATB1 localized into promyelocytic leukemia nuclear bodies where enhanced SATB1 cleavage was detected subsequent to caspase activation. These results reveal a novel sumoylation-directed caspase cleavage of this key regulatory molecule. The role of regulated proteolysis of SATB1 may be to control transcription in immune cells during normal cell functions or to assist in efficient and rapid clearance of nonfunctional or potentially damaging immune cells.
Evidence
2:
Inferred from Physical InteractionUniProtKB
The principal pathological features of Alzheimer's disease (AD) are extracellular amyloid plaques and intracellular neurofibrillary tangles, the latter composed of the microtubule-binding protein tau assembled into paired helical and straight filaments. Recent studies suggest that these pathological entities may be functionally linked, although the mechanisms by which amyloid deposition promotes pathological tau filament assembly are poorly understood. Here, we report that tau is proteolyzed by multiple caspases at a highly conserved aspartate residue (Asp421) in its C terminus in vitro and in neurons treated with amyloid-beta (Abeta) (1-42) peptide. Tau is rapidly cleaved at Asp421 in Abeta-treated neurons (within 2 h), and its proteolysis appears to precede the nuclear events of apoptosis. We also demonstrate that caspase cleavage of tau generates a truncated protein that lacks its C-terminal 20 amino acids and assembles more rapidly and more extensively into tau filaments in vitro than wild-type tau. Using a monoclonal antibody that specifically recognizes tau truncated at Asp421, we show that tau is proteolytically cleaved at this site in the fibrillar pathologies of AD brain. Taken together, our results suggest a novel mechanism linking amyloid deposition and neurofibrillary tangles in AD: Abeta peptides promote pathological tau filament assembly in neurons by triggering caspase cleavage of tau and generating a proteolytic product with enhanced polymerization kinetics.
We have developed a PCR approach to clone new apoptotic Ced-3/Ice-like cysteine protease genes. This approach uses degenerate oligonucleotides encoding the highly conserved pentapeptides QACRG and GSWFI that are present in all known apoptotic cysteine proteases. Using this approach, we have cloned a novel apoptotic gene from human Jurkat T lymphocytes. The new gene encodes a approximately 34-kilodalton protein that is highly homologous to human CPP32, Caenorhabditis elegans cell death protein CED-3, mammalian Ich-1 (Nedd2), and mammalian interleukin-1 beta converting enzyme. Because of its high homology to the C. elegans Ced-3 gene, we named the new gene mammalian Ced-3 homologue Mch2. Two Mch2 transcripts (Mch2 alpha, 1.7 kb; Mch2 beta, 1.4 kb) were detected in Jurkat T lymphocytes and other cell lines. We believe that the Mch2 alpha transcript encodes the full-length Mch2, whereas the Mch2 beta transcript encodes a shorter Mch2 isoform, probably as a result of alternative splicing. Like interleukin-1 beta converting enzyme and CPP32, recombinant Mch2 alpha, but not Mch2 beta, possesses protease activity, as determined by its ability to cleave the fluorogenic peptide DEVD-AMC. CPP32 and Mch2 alpha can also cleave poly(ADP-ribose) polymerase in vitro, suggesting that these enzymes participate in poly(ADP-ribose) polymerase cleavage observed during cellular apoptosis. In addition, overexpression of recombinant Mch2 alpha, but not Mch2 beta, induces apoptosis in Sf9 insect cells. Our data suggest that Mch2 is a Ced-3/interleukin-1 beta converting enzyme-like cysteine protease and could be another important mediator of apoptosis in mammalian cells.
The principal pathological features of Alzheimer's disease (AD) are extracellular amyloid plaques and intracellular neurofibrillary tangles, the latter composed of the microtubule-binding protein tau assembled into paired helical and straight filaments. Recent studies suggest that these pathological entities may be functionally linked, although the mechanisms by which amyloid deposition promotes pathological tau filament assembly are poorly understood. Here, we report that tau is proteolyzed by multiple caspases at a highly conserved aspartate residue (Asp421) in its C terminus in vitro and in neurons treated with amyloid-beta (Abeta) (1-42) peptide. Tau is rapidly cleaved at Asp421 in Abeta-treated neurons (within 2 h), and its proteolysis appears to precede the nuclear events of apoptosis. We also demonstrate that caspase cleavage of tau generates a truncated protein that lacks its C-terminal 20 amino acids and assembles more rapidly and more extensively into tau filaments in vitro than wild-type tau. Using a monoclonal antibody that specifically recognizes tau truncated at Asp421, we show that tau is proteolytically cleaved at this site in the fibrillar pathologies of AD brain. Taken together, our results suggest a novel mechanism linking amyloid deposition and neurofibrillary tangles in AD: Abeta peptides promote pathological tau filament assembly in neurons by triggering caspase cleavage of tau and generating a proteolytic product with enhanced polymerization kinetics.
Colorectal cancer cells are unique in that they escape Fas-mediated cell death in the presence of Fas ligand, and we recently reported that AMP-activated protein kinase-related kinase 5 (ARK5) suppresses cell death signaling mediated by cell death receptor in Akt-dependent manner. In the current study, therefore, we examined whether ARK5 is involved in the escape from Fas-mediated cell death of colorectal cancer cells. Among 10 cell lines, ARK5 mRNA expression was observed in LoVo, SW480, and SW1116 cell lines. Interestingly, SW480 and SW1116 cell lines, but not LoVo cell line, showed expressions of both Fas ligand (FasL) and Fas mRNAs. SW620 cell line also showed FasL mRNA; however, Fas and ARK5 mRNAs were not detected. Furthermore, well-coincided expression among ARK5, FasL, and Fas mRNAs was observed in tumor tissues from patients with colorectal cancer, suggesting the suppression of FasL/Fas system-induced cell death by ARK5 in colorectal cancer cell lines. Intensive cell death, which was dependent on the FasL/Fas system was encountered when ARK5 antisense RNA (ARK5/AS) was introduced into SW480 cells. FLIP was expressed in only ARK5 mRNA-expressing cell lines, and ARK5/AS induced FLIP cleavage in a caspase-6-dependent manner. Amino-acid sequence analysis of caspase-6 revealed two putative sites of phosphorylation by ARK5 at Ser80 and Ser257. Although active caspase-6 overexpression induced cell death in SW480 and DLD-1 cell lines, SW480 cells, but not DLD-1 cells, exhibited strong resistance to procaspase-6 overexpression. Moreover, mutant caspase-6, in which the Ser257 was substituted by Ala (caspase-6/SA), induced cell death and FLIP degradation, even in SW480 cells. Active ARK5 was found to phosphorylate wild-type caspase-6 in vitro, but not caspase-6/SA, and the prevented activation of caspase-6 was promoted due to its phosphorylation by active ARK5 in vitro. On the basis of the results of this study, we propose that ARK5 negatively regulates procaspase-6 by phosphorylation at Ser257, leading to resistance to the FasL/Fas system.
Protein involved in apoptotic programmed cell death. Apoptosis is characterized by cell morphological changes, including blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation and chromosomal DNA fragmentation, and eventually death. Unlike necrosis, apoptosis produces cell fragments, called apoptotic bodies, that phagocytic cells are able to engulf and quickly remove before the contents of the cell can spill out onto surrounding cells and cause damage. In general, apoptosis confers advantages during an organism's life cycle.
Enzyme which catalyzes hydrolysis reaction, i.e. the addition of the hydrogen and hydroxyl ions of water to a molecule with its consequent splitting into two or more simpler molecules.
Proteolytic enzyme with a cysteine residue (Cys) in its active site. There are many families of thiol proteases. The most well known one is the papain family (C1 in MEROPS classification) which is known to exist in most eukaryotes.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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