{"id":21510,"date":"2023-09-07T10:47:08","date_gmt":"2023-09-07T14:47:08","guid":{"rendered":"http:\/\/www.bumc.bu.edu\/ppb\/?page_id=21510"},"modified":"2025-01-02T10:11:24","modified_gmt":"2025-01-02T15:11:24","slug":"apoptosome","status":"publish","type":"page","link":"https:\/\/www.bumc.bu.edu\/ppb\/apoptosome\/","title":{"rendered":""},"content":{"rendered":"

The apoptosome: a cell death signaling platform<\/h4>\n

In the intrinsic death pathway, cytochrome c binds to Apaf-1 and triggers apoptosome assembly in the presence of dATP. This platform binds procaspase-9, which activates procaspase-3 and other downstream procaspases. To understand this process, we determined a structure of the active pc-9 human apoptosome at near atomic resolution and created a model of this heptameric platform, which contains 49 domains, 7 cytochrome c molecules and 3-4 well ordered pc-9 CARDs. Further studies of the active apoptosome should provide additional insights into the assembly and function of this cell killer, which has a complicated and still mysterious activation program. In parallel studies, we determined a near atomic structure of the Drosophila Apaf-1 related killer (Dark) in the ground state. A comparison of human and Drosophila apoptosome structures provides a possible explanation for their nucleotide preferences.<\/p>\n

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(left) Density map of the active apoptosome with bound procaspase-9 CARDs forming a helical disk-like spiral on the c7 axis. (right) Close-up view of the central hub with ribbon models for Apaf-1 and pc-9 CARDs, Apaf-1 CARD linkers in gold density. [Cheng, T.C. et al., 2016]<\/figcaption><\/figure>\n

Click on figure for animation<\/strong><\/span><\/p>\n

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(top) Shown in ribbons representation: inactive Apaf-1 monomer transition to extended conformation that occurs upon binding cytochrome c by the sensor WD40 domains in the presence of ATP\/dATP. (bottom) Ground state and assembled conformations of Apaf-1 shown within a calculated all atom density map with cytochrome c (red) and exposed CARD (green) highlighted.<\/figcaption><\/figure>\n

Click on figure for animation of Apaf-1 conformational transition (courtesy Dr. Tat Cheng).<\/span><\/strong><\/p>\n

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Double ring of Dark subunits with D8 symmetry. (top left) Density map, (top right) Model of 8 Dark subunits in a single ring, Dark CARDs in green. (bottom) Select regions in Dark density map and model including a novel post-translational modification on a lysine. [Cheng, T.C. et al, 2017]<\/figcaption><\/figure>\n

3D map depicts cell ‘wheel of death’ in action – Futurity<\/a><\/p>\n

Selected Publications:<\/h5>\n

Dorstyn L., Akey C.W.<\/strong>, and Kumar S. (2018). New insights into apoptosome structure and function. Cell Death Differ. 2018 Jul;25(7):1194-1208. doi: 10.1038\/s41418-017-0025-z. Review. PMID: 29765111<\/p>\n

Cheng, T.C., Akey, I.V., Yuan, S., Yu, Z., Ludtke, S.J. and Akey, C.W.<\/strong> (2017). A near atomic structure of the Dark apoptosome provides insight into assembly and activation. Structure 25:40-52. doi:10.1016\/j.str.2016.11.002. PMID: 27916517<\/p>\n

Cheng, T.C., Hong, C., Akey, I.V., Yuan, S. and Akey, C.W.<\/strong> (2016). A near atomic structure of the active human apoptosome. Elife. Oct 4;5. pii: e17755. doi: 10.7554\/eLife.17755. PMID: 27697150<\/p>\n

Apoptosome PubMed listing<\/a><\/h5>\n
Apoptosome EMDB entries<\/a><\/h5>\n
<\/h5>\n","protected":false},"excerpt":{"rendered":"

The apoptosome: a cell death signaling platform In the intrinsic death pathway, cytochrome c binds to Apaf-1 and triggers apoptosome assembly in the presence of dATP. This platform binds procaspase-9, which activates procaspase-3 and other downstream procaspases. To understand this process, we determined a structure of the active pc-9 human apoptosome at near atomic resolution […]<\/p>\n","protected":false},"author":1811,"featured_media":0,"parent":0,"menu_order":53,"comment_status":"closed","ping_status":"closed","template":"page-templates\/no-sidebars.php","meta":[],"_links":{"self":[{"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/pages\/21510"}],"collection":[{"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/users\/1811"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/comments?post=21510"}],"version-history":[{"count":26,"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/pages\/21510\/revisions"}],"predecessor-version":[{"id":23603,"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/pages\/21510\/revisions\/23603"}],"wp:attachment":[{"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/media?parent=21510"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}