| Structural highlights
6hpr is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | |
| Gene: | BIRC2, API1, MIHB, RNF48 (HUMAN), UBB (HUMAN), UBE2D2, PUBC1, UBC4, UBC5B, UBCH4, UBCH5B (HUMAN) |
| Activity: | RING-type E3 ubiquitin transferase, with EC number 2.3.2.27 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[BIRC2_HUMAN] Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, mitogenic kinase signaling, and cell proliferation, as well as cell invasion and metastasis. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and regulates both canonical and non-canonical NF-kappa-B signaling by acting in opposite directions: acts as a positive regulator of the canonical pathway and suppresses constitutive activation of non-canonical NF-kappa-B signaling. The target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, RIPK2, RIPK3, RIPK4, CASP3, CASP7, CASP8, TRAF2, DIABLO/SMAC, MAP3K14/NIK, MAP3K5/ASK1, IKBKG/NEMO and MXD1/MAD1. Can also function as an E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Acts as an important regulator of innate immune signaling via regulation of Toll-like receptors (TLRs), Nodlike receptors (NLRs) and RIG-I like receptors (RLRs), collectively referred to as pattern recognition receptors (PRRs). 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. Can stimulate the transcriptional activity of E2F1. Plays a role in the modulation of the cell cycle.[1] [2] [3] [4] [5] [UB2D2_HUMAN] Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-48'-linked polyubiquitination. Mediates the selective degradation of short-lived and abnormal proteins. Functions in the E6/E6-AP-induced ubiquitination of p53/TP53. Mediates ubiquitination of PEX5 and autoubiquitination of STUB1 and TRAF6. Involved in the signal-induced conjugation and subsequent degradation of NFKBIA, FBXW2-mediated GCM1 ubiquitination and degradation, MDM2-dependent degradation of p53/TP53 and the activation of MAVS in the mitochondria by DDX58/RIG-I in response to viral infection. Essential for viral activation of IRF3.[6] [7] [8] [9] [10] [11] [12] [13] [UBB_HUMAN] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.[14] [15]
Publication Abstract from PubMed
Ubiquitin (Ub)-conjugating enzymes and Ub ligases control protein degradation and regulate many cellular processes in eukaryotes. Cellular inhibitor of apoptosis protein-1 (cIAP1) plays a central role in apoptosis and tumor necrosis factor signaling. It harbors a C-terminal RING domain that homodimerizes to recruit E2~Ub (~ denotes a thioester bond) complex to catalyze Ub transfer. Non-covalent Ub binding to the backside of the E2 Ub-conjugating enzyme UbcH5 has previously been shown to enhance RING domain activity, but the molecular basis for this enhancement is unclear. To investigate how dimeric cIAP1 RING activates E2~Ub for Ub transfer and what role non-covalently bound Ub has in Ub transfer, here we determined the crystal structure of the cIAP1 RING dimer bound to both UbcH5B covalently-linked to Ub (UbcH5B-Ub) and a non-covalent Ub to 1.7 A resolution. The structure along with biochemical analyses revealed that the cIAP1 RING domain interacts with UbcH5B-Ub and thereby promotes the formation of a closed UbcH5B-Ub conformation that primes the thioester bond for Ub transfer. We observed that the non-covalent Ub binds to the backside of UbcH5B and abuts UbcH5B's alpha1beta1-loop, which, in turn, stabilizes the closed UbcH5B-Ub conformation. Our results disclose the mechanism by which cIAP1 RING dimer activates UbcH5B~Ub and indicate that non-covalent Ub binding further stabilizes the cIAP1-UbcH5B~Ub complex in the active conformation to stimulate Ub transfer.
Structural insights into non-covalent ubiquitin activation of the cIAP1-UbcH5B~ubiquitin complex.,Patel A, Sibbet GJ, Huang DT J Biol Chem. 2018 Dec 6. pii: RA118.006045. doi: 10.1074/jbc.RA118.006045. PMID:30523153[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Samuel T, Okada K, Hyer M, Welsh K, Zapata JM, Reed JC. cIAP1 Localizes to the nuclear compartment and modulates the cell cycle. Cancer Res. 2005 Jan 1;65(1):210-8. PMID:15665297
- ↑ Xu L, Zhu J, Hu X, Zhu H, Kim HT, LaBaer J, Goldberg A, Yuan J. c-IAP1 cooperates with Myc by acting as a ubiquitin ligase for Mad1. Mol Cell. 2007 Dec 14;28(5):914-22. PMID:18082613 doi:10.1016/j.molcel.2007.10.027
- ↑ 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
- ↑ Cartier J, Berthelet J, Marivin A, Gemble S, Edmond V, Plenchette S, Lagrange B, Hammann A, Dupoux A, Delva L, Eymin B, Solary E, Dubrez L. Cellular inhibitor of apoptosis protein-1 (cIAP1) can regulate E2F1 transcription factor-mediated control of cyclin transcription. J Biol Chem. 2011 Jul 29;286(30):26406-17. doi: 10.1074/jbc.M110.191239. Epub, 2011 Jun 8. PMID:21653699 doi:10.1074/jbc.M110.191239
- ↑ Bertrand MJ, Lippens S, Staes A, Gilbert B, Roelandt R, De Medts J, Gevaert K, Declercq W, Vandenabeele P. cIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4). PLoS One. 2011;6(9):e22356. doi: 10.1371/journal.pone.0022356. Epub 2011 Sep 12. PMID:21931591 doi:10.1371/journal.pone.0022356
- ↑ Gonen H, Bercovich B, Orian A, Carrano A, Takizawa C, Yamanaka K, Pagano M, Iwai K, Ciechanover A. Identification of the ubiquitin carrier proteins, E2s, involved in signal-induced conjugation and subsequent degradation of IkappaBalpha. J Biol Chem. 1999 May 21;274(21):14823-30. PMID:10329681
- ↑ Saville MK, Sparks A, Xirodimas DP, Wardrop J, Stevenson LF, Bourdon JC, Woods YL, Lane DP. Regulation of p53 by the ubiquitin-conjugating enzymes UbcH5B/C in vivo. J Biol Chem. 2004 Oct 1;279(40):42169-81. Epub 2004 Jul 26. PMID:15280377 doi:10.1074/jbc.M403362200
- ↑ Windheim M, Peggie M, Cohen P. Two different classes of E2 ubiquitin-conjugating enzymes are required for the mono-ubiquitination of proteins and elongation by polyubiquitin chains with a specific topology. Biochem J. 2008 Feb 1;409(3):723-9. PMID:18042044 doi:10.1042/BJ20071338
- ↑ Chiang MH, Chen LF, Chen H. Ubiquitin-conjugating enzyme UBE2D2 is responsible for FBXW2 (F-box and WD repeat domain containing 2)-mediated human GCM1 (glial cell missing homolog 1) ubiquitination and degradation. Biol Reprod. 2008 Nov;79(5):914-20. doi: 10.1095/biolreprod.108.071407. Epub 2008, Aug 13. PMID:18703417 doi:10.1095/biolreprod.108.071407
- ↑ Grou CP, Carvalho AF, Pinto MP, Wiese S, Piechura H, Meyer HE, Warscheid B, Sa-Miranda C, Azevedo JE. Members of the E2D (UbcH5) family mediate the ubiquitination of the conserved cysteine of Pex5p, the peroxisomal import receptor. J Biol Chem. 2008 May 23;283(21):14190-7. doi: 10.1074/jbc.M800402200. Epub 2008 , Mar 22. PMID:18359941 doi:10.1074/jbc.M800402200
- ↑ Zeng W, Xu M, Liu S, Sun L, Chen ZJ. Key role of Ubc5 and lysine-63 polyubiquitination in viral activation of IRF3. Mol Cell. 2009 Oct 23;36(2):315-25. doi: 10.1016/j.molcel.2009.09.037. PMID:19854139 doi:10.1016/j.molcel.2009.09.037
- ↑ Zeng W, Sun L, Jiang X, Chen X, Hou F, Adhikari A, Xu M, Chen ZJ. Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity. Cell. 2010 Apr 16;141(2):315-30. doi: 10.1016/j.cell.2010.03.029. PMID:20403326 doi:10.1016/j.cell.2010.03.029
- ↑ David Y, Ziv T, Admon A, Navon A. The E2 ubiquitin conjugating enzymes direct polyubiquitination to preferred lysines. J Biol Chem. 2010 Jan 8. PMID:20061386 doi:M109.089003
- ↑ Huang F, Kirkpatrick D, Jiang X, Gygi S, Sorkin A. Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol Cell. 2006 Mar 17;21(6):737-48. PMID:16543144 doi:S1097-2765(06)00120-1
- ↑ Komander D. The emerging complexity of protein ubiquitination. Biochem Soc Trans. 2009 Oct;37(Pt 5):937-53. doi: 10.1042/BST0370937. PMID:19754430 doi:10.1042/BST0370937
- ↑ Patel A, Sibbet GJ, Huang DT. Structural insights into non-covalent ubiquitin activation of the cIAP1-UbcH5B~ubiquitin complex. J Biol Chem. 2018 Dec 6. pii: RA118.006045. doi: 10.1074/jbc.RA118.006045. PMID:30523153 doi:http://dx.doi.org/10.1074/jbc.RA118.006045
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