Ubiquitin protein ligase

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Function

Ubiquitin-protein ligase (UPL) (E3) or E3 ubiquitin-protein ligase in combination with ubiquitin-conjugating enzyme (E2) causes the attachment of ubiquitin to lysine in a target protein[1].

  • UPL XIAP or X-linked Inhibitor of Apoptosis Protein stops apoptosis induced by viral infection or by overproduction of caspases. UPL XIAP binds caspase-3, -7 and -9[2]. UPL XIAP is inhibited by Smac – a death signaling protein.
  • RING-type E3 ubiquitin transferase are E3s which do not have Zn+2 coordination[3].
  • HOIL-1 or RanBP-type and C3HC4-type zinc finger-containing protein 1 is an atypical E3 ligase which forms ester bonds between ubiquitin and Ser/Thr residues in proteins[4].
  • NEDD4-like Ubiquitin protein ligase WWP see WWP2.

Examples of E3 ubiquitin-protein ligases include Parkin

Disease

XIAP mutations cause X-linked lymphoproliferative syndrome type 2[5]. Parkin UPL has a direct causal role in neurodegenerative disorders[6]. Cereblon nonsense mutation causes autosomal recessive nonsyndromic mental retardation[7].

Relevance

Overexpression of UPL XIAP functions as tumor marker. UPL cereblon is inhibited by thalidomide[8] and Lenalidomide.

Structural highlights

UPL can contain several distinct domains like:

  • WW domains which contain 2 tryptophans which bind proline-rich peptide;
  • UBA – Ubiquitin-Associated Domain;
  • TKB – Tyrosine Kinase Binding domain;
  • C2 – an 8 β strand domain which coordinates targeting proteins toward cell membrane;
  • Cereblon is a target for thalidomide;
  • HECT – Homologous to the E6-AP C-terminus;
  • RING – Really Intersting New Gene involved in binding to E2;
  • FHA – Forkhead Associated domain recognizing phosphothreonine;
  • IBR – involved in binding to E2;
  • PHD finger – Plant Homeo Domain is 50-80 amino acid long which contains a CHC motif;
  • SRA – SET and RING-Associated domain;
  • TUDOR – a ca. 50 amino acids long and recognizes dimethylated arginine;
  • CPH – protein-protein interaction domain;
  • UBR – a ca. 70 amino acid long zinc finger-like domain;
  • CUE – a ubiquitin-binding domain.

UPL XIAP consists of 3 BIR (baculoviral IAP repeat) domains, followed by UBA (ubiquitin-binding) domain and RING (C-terminal RING finger) domain. BIR2 inhibits caspase-3 and -7. BIR3 inhibits caspase-9.

UPL contains an thioester-forming cysteine which catalyzes the transfer of ubiquitin from E2 to a substrate lysine. The surface interacting residues of UPL and the acceptor ubiquitin are shown here[9].

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For some details see

3D Structures of ubiquitin protein ligase

Ubiquitin protein ligase 3D structures


Human UPL HOIP (magenta) complex with ubiquitin (green), imidazole and Zn+2 ion (grey) 4ljo

Drag the structure with the mouse to rotate

ReferencesReferences

  1. ↑ Ardley HC, Robinson PA. E3 ubiquitin ligases. Essays Biochem. 2005;41:15-30. PMID:16250895 doi:http://dx.doi.org/10.1042/EB0410015
  2. ↑ Sakemi R, Yano H, Ogasawara S, Akiba J, Nakashima O, Fukahori S, Sata M, Kojiro M. X-linked inhibitor of apoptosis (XIAP) and XIAP-associated factor-1 expressions and their relationship to apoptosis in human hepatocellular carcinoma and non-cancerous liver tissues. Oncol Rep. 2007 Jul;18(1):65-70. PMID:17549347
  3. ↑ Metzger MB, Pruneda JN, Klevit RE, Weissman AM. RING-type E3 ligases: master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination. Biochim Biophys Acta. 2014 Jan;1843(1):47-60. PMID:23747565 doi:10.1016/j.bbamcr.2013.05.026
  4. ↑ Petrova T, Zhang J, Nanda SK, Figueras-Vadillo C, Cohen P. HOIL-1-catalysed, ester-linked ubiquitylation restricts IL-18 signaling in cytotoxic T cells but promotes TLR signalling in macrophages. FEBS J. 2021 Oct;288(20):5909-5924. PMID:33932090 doi:10.1111/febs.15896
  5. ↑ Aguilar C, Lenoir C, Lambert N, Begue B, Brousse N, Canioni D, Berrebi D, Roy M, Gerart S, Chapel H, Schwerd T, Siproudhis L, Schappi M, Al-Ahmari A, Mori M, Yamaide A, Galicier L, Neven B, Routes J, Uhlig HH, Koletzko S, Patel S, Kanegane H, Picard C, Fischer A, Bensussan NC, Ruemmele F, Hugot JP, Latour S. Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers. J Allergy Clin Immunol. 2014 Nov;134(5):1131-41.e9. doi:, 10.1016/j.jaci.2014.04.031. Epub 2014 Jun 15. PMID:24942515 doi:http://dx.doi.org/10.1016/j.jaci.2014.04.031
  6. ↑ Ardley HC, Robinson PA. The role of ubiquitin-protein ligases in neurodegenerative disease. Neurodegener Dis. 2004;1(2-3):71-87. PMID:16908979 doi:http://dx.doi.org/10.1159/000080048
  7. ↑ Xu G, Jiang X, Jaffrey SR. A mental retardation-linked nonsense mutation in cereblon is rescued by proteasome inhibition. J Biol Chem. 2013 Oct 11;288(41):29573-85. doi: 10.1074/jbc.M113.472092. Epub, 2013 Aug 27. PMID:23983124 doi:http://dx.doi.org/10.1074/jbc.M113.472092
  8. ↑ Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, Wong KK, Bradner JE, Kaelin WG Jr. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science. 2014 Jan 17;343(6168):305-9. doi: 10.1126/science.1244917. Epub 2013 Nov, 29. PMID:24292623 doi:http://dx.doi.org/10.1126/science.1244917
  9. ↑ Stieglitz B, Rana RR, Koliopoulos MG, Morris-Davies AC, Schaeffer V, Christodoulou E, Howell S, Brown NR, Dikic I, Rittinger K. Structural basis for ligase-specific conjugation of linear ubiquitin chains by HOIP. Nature. 2013 Oct 20. doi: 10.1038/nature12638. PMID:24141947 doi:http://dx.doi.org/10.1038/nature12638

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