3siq

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Crystal Structure of autoinhibited dIAP1-BIR1 domain

Structural highlights

3siq is a 6 chain structure with sequence from Drosophila melanogaster. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.4Å
Ligands:ZN
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DIAP1_DROME Anti-apoptotic protein which functions as a caspase regulator, using its E3 ubiquitin-protein ligase activity to smother caspase activity. Binds, ubiquitinates and inactivates initiator caspase Dronc, and effector caspases Drice and Dcp-1. Acts as a Nedd8-E3 ubiquitin-protein ligase for Drice. Suppresses apoptosis by targeting the apoptosome for ubiquitination and inactivation. Plays an important role in cell motility. Overexpression suppresses rpr and hid-dependent cell death in the eye. Interaction of Diap1 with Dronc is required to suppress Dronc-mediated cell death through Diap1-mediated ubiquitination of Dronc. Acts as a positive regulator of Wnt signaling.[1] [2] [3] [4] [5] [6]

Publication Abstract from PubMed

The Drosophila inhibitor of apoptosis protein DIAP1 exists in an auto-inhibited conformation, unable to suppress the effector caspase drICE. Auto-inhibition is disabled by caspase-mediated cleavage of DIAP1 after Asp20. The cleaved DIAP1 binds to mature drICE, inhibits its protease activity, and, presumably, also targets drICE for ubiquitylation. DIAP1-mediated suppression of drICE is effectively antagonized by the pro-apoptotic proteins Reaper, Hid, and Grim (RHG). Despite rigorous effort, the molecular mechanisms behind these observations are enigmatic. Here we report a 2.4 A crystal structure of uncleaved DIAP1-BIR1, which reveals how the amino-terminal sequences recognize a conserved surface groove in BIR1 to achieve auto-inhibition, and a 3.5 A crystal structure of active drICE bound to cleaved DIAP1-BIR1, which provides a structural explanation to DIAP1-mediated inhibition of drICE. These structures and associated biochemical analyses, together with published reports, define the molecular determinants that govern the interplay among DIAP1, drICE and the RHG proteins.

Structural mechanisms of DIAP1 auto-inhibition and DIAP1-mediated inhibition of drICE.,Li X, Wang J, Shi Y Nat Commun. 2011 Aug 2;2:408. doi: 10.1038/ncomms1418. PMID:21811237[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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References

  1. ↑ Chai J, Yan N, Huh JR, Wu JW, Li W, Hay BA, Shi Y. Molecular mechanism of Reaper-Grim-Hid-mediated suppression of DIAP1-dependent Dronc ubiquitination. Nat Struct Biol. 2003 Nov;10(11):892-8. Epub 2003 Sep 28. PMID:14517550 doi:10.1038/nsb989
  2. ↑ Igaki T, Suzuki Y, Tokushige N, Aonuma H, Takahashi R, Miura M. Evolution of mitochondrial cell death pathway: Proapoptotic role of HtrA2/Omi in Drosophila. Biochem Biophys Res Commun. 2007 May 18;356(4):993-7. Epub 2007 Mar 26. PMID:17397804 doi:10.1016/j.bbrc.2007.03.079
  3. ↑ Khan FS, Fujioka M, Datta P, Fernandes-Alnemri T, Jaynes JB, Alnemri ES. The interaction of DIAP1 with dOmi/HtrA2 regulates cell death in Drosophila. Cell Death Differ. 2008 Jun;15(6):1073-83. doi: 10.1038/cdd.2008.19. Epub 2008, Feb 15. PMID:18259196 doi:10.1038/cdd.2008.19
  4. ↑ Broemer M, Tenev T, Rigbolt KT, Hempel S, Blagoev B, Silke J, Ditzel M, Meier P. Systematic in vivo RNAi analysis identifies IAPs as NEDD8-E3 ligases. Mol Cell. 2010 Dec 10;40(5):810-22. doi: 10.1016/j.molcel.2010.11.011. PMID:21145488 doi:10.1016/j.molcel.2010.11.011
  5. ↑ Hanson AJ, Wallace HA, Freeman TJ, Beauchamp RD, Lee LA, Lee E. XIAP monoubiquitylates Groucho/TLE to promote canonical Wnt signaling. Mol Cell. 2012 Mar 9;45(5):619-28. doi: 10.1016/j.molcel.2011.12.032. Epub 2012, Feb 1. PMID:22304967 doi:10.1016/j.molcel.2011.12.032
  6. ↑ Hay BA, Wassarman DA, Rubin GM. Drosophila homologs of baculovirus inhibitor of apoptosis proteins function to block cell death. Cell. 1995 Dec 29;83(7):1253-62. PMID:8548811
  7. ↑ Li X, Wang J, Shi Y. Structural mechanisms of DIAP1 auto-inhibition and DIAP1-mediated inhibition of drICE. Nat Commun. 2011 Aug 2;2:408. doi: 10.1038/ncomms1418. PMID:21811237 doi:10.1038/ncomms1418

Contents


PDB ID 3siq

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OCA

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