5jul | pdb_00005jul
Near atomic structure of the Dark apoptosome
Structural highlights
FunctionAPAF_DROME Main component of the apoptosome, an adapter protein complex that mediates activation of the caspase cascade in programmed cell death initiated by the intrinsic apoptosis pathway (PubMed:10984473, PubMed:16310803, PubMed:21220123, PubMed:25644603, PubMed:27916517). Recruits the initiator caspase Dronc, promoting its autocatalytic cleavage and activation; triggers the caspase cascade upstream of the effector caspases Drice and dcp-1 (PubMed:10619022, PubMed:10619023, PubMed:10984473, PubMed:21220123, PubMed:25644603). Effector of reaper, grim and hid induced cell killing (PubMed:10559939, PubMed:10619023, PubMed:16645639). Produces at least two isoforms that may activate distinct caspases by separate pathways (PubMed:10619023). Nucleotide binding protein with strong specificity for dATP; dATP binding is not essential, but promotes homooligomerization to form the apoptosome complex (PubMed:10619022, PubMed:10619023, PubMed:16310803, PubMed:21220123, PubMed:25644603, PubMed:27916517). There is currently no evidence of dATPase activity and structural analysis of the nucleotide binding pocket suggests negligible to no dATPase activity (Probable). Caspase activation by the apoptosome was initially thought to be dependent on binding of cytochrome c released from mitochondria, as is the case for vertebrate orthologs (PubMed:10619022, PubMed:10619023). Apoptosis induction by the Dark apoptosome appears to be cytochrome c independent (PubMed:11901172). Required for stress-induced apoptosis, for example in response to radiation (UV or gamma) or treatment with macromolecular synthesis inhibitors like cycloheximide and actinomycin D (PubMed:11901172, PubMed:16533943). Required for most, but not all programmed cell death during embryonic development (PubMed:16645639). Involved in developmental cell number regulation by apoptosis, particularly during neuronal and sensory organ development (PubMed:10559939, PubMed:10619022, PubMed:10619023, PubMed:16533943, PubMed:16645639). Involved in reduction of midline glial cell numbers by programmed cell death during embryogenesis (PubMed:16645639). During metamorphosis involved in removal of larval salivary glands by programmed cell death, but not of the larval midgut (PubMed:16533943).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] Publication Abstract from PubMedIn Drosophila, the Apaf-1-related killer (Dark) forms an apoptosome that activates procaspases. To investigate function, we have determined a near-atomic structure of Dark double rings using cryo-electron microscopy. We then built a nearly complete model of the apoptosome that includes 7- and 8-blade beta-propellers. We find that the preference for dATP during Dark assembly may be governed by Ser325, which is in close proximity to the 2' carbon of the deoxyribose ring. Interestingly, beta-propellers in V-shaped domains of the Dark apoptosome are more widely separated, relative to these features in the Apaf-1 apoptosome. This wider spacing may be responsible for the lack of cytochrome c binding to beta-propellers in the Dark apoptosome. Our structure also highlights the roles of two loss-of-function mutations that may block Dark assembly. Finally, the improved model provides a framework to understand apical procaspase activation in the intrinsic cell death pathway. A Near-Atomic Structure of the Dark Apoptosome Provides Insight into Assembly and Activation.,Cheng TC, Akey IV, Yuan S, Yu Z, Ludtke SJ, Akey CW Structure. 2017 Jan 3;25(1):40-52. doi: 10.1016/j.str.2016.11.002. Epub 2016 Dec , 1. PMID:27916517[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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