| Structural highlights
Disease
[XIAP_HUMAN] Defects in XIAP are the cause of lymphoproliferative syndrome X-linked type 2 (XLP2) [MIM:300635]. XLP is a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Symptoms include severe or fatal mononucleosis, acquired hypogammaglobulinemia, pancytopenia and malignant lymphoma.[1]
Function
[XIAP_HUMAN] Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis. Acts as a direct caspase inhibitor. Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry. Inactivates CASP9 by keeping it in a monomeric, inactive state. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and the target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, CASP3, CASP7, CASP8, CASP9, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS and BIRC5/survivin. Ubiquitinion of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation. Ubiquitinion of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation. Plays a role in copper homeostasis by ubiquitinationg COMMD1 and promoting its proteasomal degradation. Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation. Acts as an important regulator of innate immune signaling via regulation of Nodlike receptors (NLRs). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase-dependent and caspase-independent manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8. Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES. Ubiquitination of TLE3 results in inhibition of its interaction with TCF7L2/TCF4 thereby allowing efficient recruitment and binding of the transcriptional coactivator beta-catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific transcriptional program.[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
Publication Abstract from PubMed
To develop novel inhibitor of apoptosis (IAP) proteins antagonists, we designed a bicyclic octahydropyrrolo[1,2-a]pyrazine scaffold as a novel proline bioisostere. This design was based on the X-ray co-crystal structure of four N-terminal amino acid residues (AVPI) of the second mitochondria-derived activator of caspase (Smac) with the X-chromosome-linked IAP (XIAP) protein. Lead optimization of this scaffold to improve oral absorption yielded compound 45, which showed potent cellular IAP1 (cIAP1 IC50: 1.3 nM) and XIAP (IC50: 200 nM) inhibitory activity, in addition to potent tumor growth inhibitory activity (GI50: 1.8 nM) in MDA-MB-231 breast cancer cells. X-ray crystallographic analysis of compound 45 bound to XIAP and to cIAP1 was achieved, revealing the various key interactions that contribute to the higher cIAPI affinity of compound 45 over XIAP. Due to its potent IAP inhibitory activities, compound 45 (T-3256336) caused tumor regression in a MDA-MB-231 tumor xenograft model (T/C: -53% at 30 mg/kg).
Design and Synthesis of Potent Inhibitor of Apoptosis (IAP) Proteins Antagonists Bearing an Octahydropyrrolo[1,2-a]pyrazine Scaffold as a Novel Proline Mimetic.,Hashimoto K, Saito B, Miyamoto N, Oguro Y, Tomita D, Shiokawa Z, Asano M, Kakei H, Taya N, Kawasaki M, Sumi H, Yabuki M, Iwai K, Yoshida S, Yoshimatsu M, Aoyama K, Kosugi Y, Kojima T, Morishita N, Dougan DR, Snell GP, Imamura S, Ishikawa T J Med Chem. 2013 Jan 8. PMID:23298277[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Rigaud S, Fondaneche MC, Lambert N, Pasquier B, Mateo V, Soulas P, Galicier L, Le Deist F, Rieux-Laucat F, Revy P, Fischer A, de Saint Basile G, Latour S. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature. 2006 Nov 2;444(7115):110-4. PMID:17080092 doi:nature05257
- ↑ Deveraux QL, Takahashi R, Salvesen GS, Reed JC. X-linked IAP is a direct inhibitor of cell-death proteases. Nature. 1997 Jul 17;388(6639):300-4. PMID:9230442 doi:10.1038/40901
- ↑ Suzuki Y, Nakabayashi Y, Takahashi R. Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death. Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8662-7. Epub 2001 Jul 10. PMID:11447297 doi:10.1073/pnas.161506698
- ↑ MacFarlane M, Merrison W, Bratton SB, Cohen GM. Proteasome-mediated degradation of Smac during apoptosis: XIAP promotes Smac ubiquitination in vitro. J Biol Chem. 2002 Sep 27;277(39):36611-6. Epub 2002 Jul 16. PMID:12121969 doi:10.1074/jbc.M200317200
- ↑ Burstein E, Ganesh L, Dick RD, van De Sluis B, Wilkinson JC, Klomp LW, Wijmenga C, Brewer GJ, Nabel GJ, Duckett CS. A novel role for XIAP in copper homeostasis through regulation of MURR1. EMBO J. 2004 Jan 14;23(1):244-54. Epub 2003 Dec 18. PMID:14685266 doi:10.1038/sj.emboj.7600031
- ↑ Dan HC, Sun M, Kaneko S, Feldman RI, Nicosia SV, Wang HG, Tsang BK, Cheng JQ. Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein (XIAP). J Biol Chem. 2004 Feb 13;279(7):5405-12. Epub 2003 Nov 25. PMID:14645242 doi:10.1074/jbc.M312044200
- ↑ Wilkinson JC, Wilkinson AS, Galban S, Csomos RA, Duckett CS. Apoptosis-inducing factor is a target for ubiquitination through interaction with XIAP. Mol Cell Biol. 2008 Jan;28(1):237-47. Epub 2007 Oct 29. PMID:17967870 doi:MCB.01065-07
- ↑ Van Themsche C, Leblanc V, Parent S, Asselin E. X-linked inhibitor of apoptosis protein (XIAP) regulates PTEN ubiquitination, content, and compartmentalization. J Biol Chem. 2009 Jul 31;284(31):20462-6. doi: 10.1074/jbc.C109.009522. Epub 2009, May 27. PMID:19473982 doi:10.1074/jbc.C109.009522
- ↑ 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
- ↑ Brady GF, Galban S, Liu X, Basrur V, Gitlin JD, Elenitoba-Johnson KS, Wilson TE, Duckett CS. Regulation of the copper chaperone CCS by XIAP-mediated ubiquitination. Mol Cell Biol. 2010 Apr;30(8):1923-36. doi: 10.1128/MCB.00900-09. Epub 2010 Feb, 12. PMID:20154138 doi:10.1128/MCB.00900-09
- ↑ Lewis EM, Wilkinson AS, Davis NY, Horita DA, Wilkinson JC. Nondegradative ubiquitination of apoptosis inducing factor (AIF) by X-linked inhibitor of apoptosis at a residue critical for AIF-mediated chromatin degradation. Biochemistry. 2011 Dec 27;50(51):11084-96. doi: 10.1021/bi201483g. Epub 2011 Dec , 2. PMID:22103349 doi:10.1021/bi201483g
- ↑ 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
- ↑ Lu M, Lin SC, Huang Y, Kang YJ, Rich R, Lo YC, Myszka D, Han J, Wu H. XIAP induces NF-kappaB activation via the BIR1/TAB1 interaction and BIR1 dimerization. Mol Cell. 2007 Jun 8;26(5):689-702. PMID:17560374 doi:http://dx.doi.org/10.1016/j.molcel.2007.05.006
- ↑ Hashimoto K, Saito B, Miyamoto N, Oguro Y, Tomita D, Shiokawa Z, Asano M, Kakei H, Taya N, Kawasaki M, Sumi H, Yabuki M, Iwai K, Yoshida S, Yoshimatsu M, Aoyama K, Kosugi Y, Kojima T, Morishita N, Dougan DR, Snell GP, Imamura S, Ishikawa T. Design and Synthesis of Potent Inhibitor of Apoptosis (IAP) Proteins Antagonists Bearing an Octahydropyrrolo[1,2-a]pyrazine Scaffold as a Novel Proline Mimetic. J Med Chem. 2013 Jan 8. PMID:23298277 doi:10.1021/jm301674z
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