Maintenance of Caspase-3 Proenzyme Dormancy by an Intrinsic "Safety Catch" Regulatory Tripeptide
Caspase-3 is synthesized as a dormant proenzyme and is maintained in an inactive conformation by an Asp-Asp-Asp "safety-catch" regulatory tripeptide contained within a flexible loop near the large-subunit/small-subunit junction. Removal of this "safety catch" results in substanti...
Gespeichert in:
| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2001-05, Vol.98 (11), p.6132-6137 |
|---|---|
| Hauptverfasser: | , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 6137 |
|---|---|
| container_issue | 11 |
| container_start_page | 6132 |
| container_title | Proceedings of the National Academy of Sciences - PNAS |
| container_volume | 98 |
| creator | Roy, Sophie Bayly, Christopher I. Gareau, Yves Houtzager, Vicky M. Kargman, Stacia Sabina L. C. Keen Rowland, Kathleen Seiden, Isolde M. Thornberry, Nancy A. Nicholson, Donald W. |
| description | Caspase-3 is synthesized as a dormant proenzyme and is maintained in an inactive conformation by an Asp-Asp-Asp "safety-catch" regulatory tripeptide contained within a flexible loop near the large-subunit/small-subunit junction. Removal of this "safety catch" results in substantially enhanced autocatalytic maturation as well as increased vulnerability to proteolytic activation by upstream proteases in the apoptotic pathway such as caspase-9 and granzyme B. The safety catch functions through multiple ionic interactions that are disrupted by acidification, which occurs in the cytosol of cells during the early stages of apoptosis. We propose that the caspase-3 safety catch is a key regulatory checkpoint in the apoptotic cascade that regulates terminal events in the caspase cascade by modulating the triggering of caspase-3 activation. |
| doi_str_mv | 10.1073/pnas.111085198 |
| format | Article |
| fullrecord | <record><control><sourceid>jstor_proqu</sourceid><recordid>TN_cdi_proquest_miscellaneous_70878116</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><jstor_id>3055771</jstor_id><sourcerecordid>3055771</sourcerecordid><originalsourceid>FETCH-LOGICAL-c489t-7f11ea59b14c07036d035056b0b505a0a0372fbb4dae1e7da1b649ff483245133</originalsourceid><addsrcrecordid>eNp9kc2P0zAQxS0EYkvhygkhqwc4pczETuxIe0Hla6VFIFjOxkmc3VSpHWwHEf56XLWUhQOawxze743e6BHyGGGNINiL0eqwRkSQBVbyDlkgVJiVvIK7ZAGQi0zynJ-RByFsAaAqJNwnZ4isYJLjgnx9r3sbjdW2MdR1dKPDqIPJGP3onbE_552hr5zfJX2m9Uy1pRc2-t6GvqGrz7ozcU6m2Nys6CdzPQ06Oj_TK9-PZox9ax6Se50egnl03Evy5c3rq8277PLD24vNy8us4bKKmegQjS6qGnkDAljZAiugKGuo09KggYm8q2veaoNGtBrr9GTXcclyXiBjS3J-uDtO9c60jUkp9aBG3--0n5XTvfpbsf2NunbfFWM8zZI8O9q9-zaZENWuD40ZBm2Nm4ISIIVELBO4-gfcusnb9JrKAZkEVlUJWh-gxrsQvOlOORDUvje1702dekuGp7fT_8GPRd0C9sbfciUToUpkeQKe_xdQ3TQM0fyIiXxyILchdXVCGRSFEMh-AZs2tSg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>201380399</pqid></control><display><type>article</type><title>Maintenance of Caspase-3 Proenzyme Dormancy by an Intrinsic "Safety Catch" Regulatory Tripeptide</title><source>Jstor Complete Legacy</source><source>MEDLINE</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><source>Free Full-Text Journals in Chemistry</source><creator>Roy, Sophie ; Bayly, Christopher I. ; Gareau, Yves ; Houtzager, Vicky M. ; Kargman, Stacia ; Sabina L. C. Keen ; Rowland, Kathleen ; Seiden, Isolde M. ; Thornberry, Nancy A. ; Nicholson, Donald W.</creator><creatorcontrib>Roy, Sophie ; Bayly, Christopher I. ; Gareau, Yves ; Houtzager, Vicky M. ; Kargman, Stacia ; Sabina L. C. Keen ; Rowland, Kathleen ; Seiden, Isolde M. ; Thornberry, Nancy A. ; Nicholson, Donald W.</creatorcontrib><description>Caspase-3 is synthesized as a dormant proenzyme and is maintained in an inactive conformation by an Asp-Asp-Asp "safety-catch" regulatory tripeptide contained within a flexible loop near the large-subunit/small-subunit junction. Removal of this "safety catch" results in substantially enhanced autocatalytic maturation as well as increased vulnerability to proteolytic activation by upstream proteases in the apoptotic pathway such as caspase-9 and granzyme B. The safety catch functions through multiple ionic interactions that are disrupted by acidification, which occurs in the cytosol of cells during the early stages of apoptosis. We propose that the caspase-3 safety catch is a key regulatory checkpoint in the apoptotic cascade that regulates terminal events in the caspase cascade by modulating the triggering of caspase-3 activation.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.111085198</identifier><identifier>PMID: 11353841</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Acidification ; Amino Acid Sequence ; Apoptosis ; Bacteria ; Biochemistry ; Biological Sciences ; Caspase 3 ; Caspase 8 ; Caspase 9 ; Caspase Inhibitors ; Caspases - chemistry ; Caspases - metabolism ; Catalysis ; Catalytic activity ; Cell death ; Cellular biology ; Cysteine Proteinase Inhibitors - pharmacology ; Cytosol ; Dormancy ; Enzyme Activation ; Enzyme Precursors - antagonists & inhibitors ; Enzyme Precursors - chemistry ; Enzymes ; Humans ; Hydrogen-Ion Concentration ; Intracellular Fluid ; Models, Molecular ; Molecular Sequence Data ; Peptides ; Peptides - pharmacology ; Protein Structure, Secondary ; T lymphocytes ; Transfection</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2001-05, Vol.98 (11), p.6132-6137</ispartof><rights>Copyright 1993-2001 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences May 22, 2001</rights><rights>Copyright © 2001, The National Academy of Sciences 2001</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c489t-7f11ea59b14c07036d035056b0b505a0a0372fbb4dae1e7da1b649ff483245133</citedby><cites>FETCH-LOGICAL-c489t-7f11ea59b14c07036d035056b0b505a0a0372fbb4dae1e7da1b649ff483245133</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/98/11.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3055771$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3055771$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11353841$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Roy, Sophie</creatorcontrib><creatorcontrib>Bayly, Christopher I.</creatorcontrib><creatorcontrib>Gareau, Yves</creatorcontrib><creatorcontrib>Houtzager, Vicky M.</creatorcontrib><creatorcontrib>Kargman, Stacia</creatorcontrib><creatorcontrib>Sabina L. C. Keen</creatorcontrib><creatorcontrib>Rowland, Kathleen</creatorcontrib><creatorcontrib>Seiden, Isolde M.</creatorcontrib><creatorcontrib>Thornberry, Nancy A.</creatorcontrib><creatorcontrib>Nicholson, Donald W.</creatorcontrib><title>Maintenance of Caspase-3 Proenzyme Dormancy by an Intrinsic "Safety Catch" Regulatory Tripeptide</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Caspase-3 is synthesized as a dormant proenzyme and is maintained in an inactive conformation by an Asp-Asp-Asp "safety-catch" regulatory tripeptide contained within a flexible loop near the large-subunit/small-subunit junction. Removal of this "safety catch" results in substantially enhanced autocatalytic maturation as well as increased vulnerability to proteolytic activation by upstream proteases in the apoptotic pathway such as caspase-9 and granzyme B. The safety catch functions through multiple ionic interactions that are disrupted by acidification, which occurs in the cytosol of cells during the early stages of apoptosis. We propose that the caspase-3 safety catch is a key regulatory checkpoint in the apoptotic cascade that regulates terminal events in the caspase cascade by modulating the triggering of caspase-3 activation.</description><subject>Acidification</subject><subject>Amino Acid Sequence</subject><subject>Apoptosis</subject><subject>Bacteria</subject><subject>Biochemistry</subject><subject>Biological Sciences</subject><subject>Caspase 3</subject><subject>Caspase 8</subject><subject>Caspase 9</subject><subject>Caspase Inhibitors</subject><subject>Caspases - chemistry</subject><subject>Caspases - metabolism</subject><subject>Catalysis</subject><subject>Catalytic activity</subject><subject>Cell death</subject><subject>Cellular biology</subject><subject>Cysteine Proteinase Inhibitors - pharmacology</subject><subject>Cytosol</subject><subject>Dormancy</subject><subject>Enzyme Activation</subject><subject>Enzyme Precursors - antagonists & inhibitors</subject><subject>Enzyme Precursors - chemistry</subject><subject>Enzymes</subject><subject>Humans</subject><subject>Hydrogen-Ion Concentration</subject><subject>Intracellular Fluid</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>Peptides</subject><subject>Peptides - pharmacology</subject><subject>Protein Structure, Secondary</subject><subject>T lymphocytes</subject><subject>Transfection</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc2P0zAQxS0EYkvhygkhqwc4pczETuxIe0Hla6VFIFjOxkmc3VSpHWwHEf56XLWUhQOawxze743e6BHyGGGNINiL0eqwRkSQBVbyDlkgVJiVvIK7ZAGQi0zynJ-RByFsAaAqJNwnZ4isYJLjgnx9r3sbjdW2MdR1dKPDqIPJGP3onbE_552hr5zfJX2m9Uy1pRc2-t6GvqGrz7ozcU6m2Nys6CdzPQ06Oj_TK9-PZox9ax6Se50egnl03Evy5c3rq8277PLD24vNy8us4bKKmegQjS6qGnkDAljZAiugKGuo09KggYm8q2veaoNGtBrr9GTXcclyXiBjS3J-uDtO9c60jUkp9aBG3--0n5XTvfpbsf2NunbfFWM8zZI8O9q9-zaZENWuD40ZBm2Nm4ISIIVELBO4-gfcusnb9JrKAZkEVlUJWh-gxrsQvOlOORDUvje1702dekuGp7fT_8GPRd0C9sbfciUToUpkeQKe_xdQ3TQM0fyIiXxyILchdXVCGRSFEMh-AZs2tSg</recordid><startdate>20010522</startdate><enddate>20010522</enddate><creator>Roy, Sophie</creator><creator>Bayly, Christopher I.</creator><creator>Gareau, Yves</creator><creator>Houtzager, Vicky M.</creator><creator>Kargman, Stacia</creator><creator>Sabina L. C. Keen</creator><creator>Rowland, Kathleen</creator><creator>Seiden, Isolde M.</creator><creator>Thornberry, Nancy A.</creator><creator>Nicholson, Donald W.</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><general>The National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20010522</creationdate><title>Maintenance of Caspase-3 Proenzyme Dormancy by an Intrinsic "Safety Catch" Regulatory Tripeptide</title><author>Roy, Sophie ; Bayly, Christopher I. ; Gareau, Yves ; Houtzager, Vicky M. ; Kargman, Stacia ; Sabina L. C. Keen ; Rowland, Kathleen ; Seiden, Isolde M. ; Thornberry, Nancy A. ; Nicholson, Donald W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c489t-7f11ea59b14c07036d035056b0b505a0a0372fbb4dae1e7da1b649ff483245133</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Acidification</topic><topic>Amino Acid Sequence</topic><topic>Apoptosis</topic><topic>Bacteria</topic><topic>Biochemistry</topic><topic>Biological Sciences</topic><topic>Caspase 3</topic><topic>Caspase 8</topic><topic>Caspase 9</topic><topic>Caspase Inhibitors</topic><topic>Caspases - chemistry</topic><topic>Caspases - metabolism</topic><topic>Catalysis</topic><topic>Catalytic activity</topic><topic>Cell death</topic><topic>Cellular biology</topic><topic>Cysteine Proteinase Inhibitors - pharmacology</topic><topic>Cytosol</topic><topic>Dormancy</topic><topic>Enzyme Activation</topic><topic>Enzyme Precursors - antagonists & inhibitors</topic><topic>Enzyme Precursors - chemistry</topic><topic>Enzymes</topic><topic>Humans</topic><topic>Hydrogen-Ion Concentration</topic><topic>Intracellular Fluid</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>Peptides</topic><topic>Peptides - pharmacology</topic><topic>Protein Structure, Secondary</topic><topic>T lymphocytes</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Roy, Sophie</creatorcontrib><creatorcontrib>Bayly, Christopher I.</creatorcontrib><creatorcontrib>Gareau, Yves</creatorcontrib><creatorcontrib>Houtzager, Vicky M.</creatorcontrib><creatorcontrib>Kargman, Stacia</creatorcontrib><creatorcontrib>Sabina L. C. Keen</creatorcontrib><creatorcontrib>Rowland, Kathleen</creatorcontrib><creatorcontrib>Seiden, Isolde M.</creatorcontrib><creatorcontrib>Thornberry, Nancy A.</creatorcontrib><creatorcontrib>Nicholson, Donald W.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Roy, Sophie</au><au>Bayly, Christopher I.</au><au>Gareau, Yves</au><au>Houtzager, Vicky M.</au><au>Kargman, Stacia</au><au>Sabina L. C. Keen</au><au>Rowland, Kathleen</au><au>Seiden, Isolde M.</au><au>Thornberry, Nancy A.</au><au>Nicholson, Donald W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Maintenance of Caspase-3 Proenzyme Dormancy by an Intrinsic "Safety Catch" Regulatory Tripeptide</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2001-05-22</date><risdate>2001</risdate><volume>98</volume><issue>11</issue><spage>6132</spage><epage>6137</epage><pages>6132-6137</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Caspase-3 is synthesized as a dormant proenzyme and is maintained in an inactive conformation by an Asp-Asp-Asp "safety-catch" regulatory tripeptide contained within a flexible loop near the large-subunit/small-subunit junction. Removal of this "safety catch" results in substantially enhanced autocatalytic maturation as well as increased vulnerability to proteolytic activation by upstream proteases in the apoptotic pathway such as caspase-9 and granzyme B. The safety catch functions through multiple ionic interactions that are disrupted by acidification, which occurs in the cytosol of cells during the early stages of apoptosis. We propose that the caspase-3 safety catch is a key regulatory checkpoint in the apoptotic cascade that regulates terminal events in the caspase cascade by modulating the triggering of caspase-3 activation.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>11353841</pmid><doi>10.1073/pnas.111085198</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0027-8424 |
| ispartof | Proceedings of the National Academy of Sciences - PNAS, 2001-05, Vol.98 (11), p.6132-6137 |
| issn | 0027-8424 1091-6490 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_70878116 |
| source | Jstor Complete Legacy; MEDLINE; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Acidification Amino Acid Sequence Apoptosis Bacteria Biochemistry Biological Sciences Caspase 3 Caspase 8 Caspase 9 Caspase Inhibitors Caspases - chemistry Caspases - metabolism Catalysis Catalytic activity Cell death Cellular biology Cysteine Proteinase Inhibitors - pharmacology Cytosol Dormancy Enzyme Activation Enzyme Precursors - antagonists & inhibitors Enzyme Precursors - chemistry Enzymes Humans Hydrogen-Ion Concentration Intracellular Fluid Models, Molecular Molecular Sequence Data Peptides Peptides - pharmacology Protein Structure, Secondary T lymphocytes Transfection |
| title | Maintenance of Caspase-3 Proenzyme Dormancy by an Intrinsic "Safety Catch" Regulatory Tripeptide |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-11T04%3A35%3A20IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-jstor_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Maintenance%20of%20Caspase-3%20Proenzyme%20Dormancy%20by%20an%20Intrinsic%20%22Safety%20Catch%22%20Regulatory%20Tripeptide&rft.jtitle=Proceedings%20of%20the%20National%20Academy%20of%20Sciences%20-%20PNAS&rft.au=Roy,%20Sophie&rft.date=2001-05-22&rft.volume=98&rft.issue=11&rft.spage=6132&rft.epage=6137&rft.pages=6132-6137&rft.issn=0027-8424&rft.eissn=1091-6490&rft_id=info:doi/10.1073/pnas.111085198&rft_dat=%3Cjstor_proqu%3E3055771%3C/jstor_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=201380399&rft_id=info:pmid/11353841&rft_jstor_id=3055771&rfr_iscdi=true |