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Biochem J. May 1, 2004; 379(Pt 3): 513–525.
PMCID: PMC1224133

Getting into position: the catalytic mechanisms of protein ubiquitylation.


The role of protein ubiquitylation in the control of diverse cellular pathways has recently gained widespread attention. Ubiquitylation not only directs the targeted destruction of tagged proteins by the 26 S proteasome, but it also modulates protein activities, protein-protein interactions and subcellular localization. An understanding of the components involved in protein ubiquitylation (E1s, E2s and E3s) is essential to understand how specificity and regulation are conferred upon these pathways. Much of what we know about the catalytic mechanisms of protein ubiquitylation comes from structural studies of the proteins involved in this process. Indeed, structures of ubiquitin-activating enzymes (E1s) and ubiquitin-conjugating enzymes (E2s) have provided insight into their mechanistic details. E3s (ubiquitin ligases) contain most of the substrate specificity and regulatory elements required for protein ubiquitylation. Although several E3 structures are available, the specific mechanistic role of E3s is still unclear. This review will discuss the different types of ubiquitin signals and how they are generated. Recent advances in the field of protein ubiquitylation will be examined, including the mechanisms of E1, E2 and E3. In particular, we discuss the complexity of molecular recognition required to impose selectivity on substrate selection and topology of poly-ubiquitin chains.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Johnson LN, Lewis RJ. Structural basis for control by phosphorylation. Chem Rev. 2001 Aug;101(8):2209–2242. [PubMed]
  • Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem. 1998;67:425–479. [PubMed]
  • Kloetzel PM. Antigen processing by the proteasome. Nat Rev Mol Cell Biol. 2001 Mar;2(3):179–187. [PubMed]
  • Jesenberger Veronika, Jentsch Stefan. Deadly encounter: ubiquitin meets apoptosis. Nat Rev Mol Cell Biol. 2002 Feb;3(2):112–121. [PubMed]
  • Hicke Linda, Dunn Rebecca. Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins. Annu Rev Cell Dev Biol. 2003;19:141–172. [PubMed]
  • Muratani Masafumi, Tansey William P. How the ubiquitin-proteasome system controls transcription. Nat Rev Mol Cell Biol. 2003 Mar;4(3):192–201. [PubMed]
  • Reed Steven I. Ratchets and clocks: the cell cycle, ubiquitylation and protein turnover. Nat Rev Mol Cell Biol. 2003 Nov;4(11):855–864. [PubMed]
  • Arnason T, Ellison MJ. Stress resistance in Saccharomyces cerevisiae is strongly correlated with assembly of a novel type of multiubiquitin chain. Mol Cell Biol. 1994 Dec;14(12):7876–7883. [PMC free article] [PubMed]
  • Johnson ES, Ma PC, Ota IM, Varshavsky A. A proteolytic pathway that recognizes ubiquitin as a degradation signal. J Biol Chem. 1995 Jul 21;270(29):17442–17456. [PubMed]
  • Spence J, Sadis S, Haas AL, Finley D. A ubiquitin mutant with specific defects in DNA repair and multiubiquitination. Mol Cell Biol. 1995 Mar;15(3):1265–1273. [PMC free article] [PubMed]
  • Baboshina OV, Haas AL. Novel multiubiquitin chain linkages catalyzed by the conjugating enzymes E2EPF and RAD6 are recognized by 26 S proteasome subunit 5. J Biol Chem. 1996 Feb 2;271(5):2823–2831. [PubMed]
  • Peng Junmin, Schwartz Daniel, Elias Joshua E, Thoreen Carson C, Cheng Dongmei, Marsischky Gerald, Roelofs Jeroen, Finley Daniel, Gygi Steven P. A proteomics approach to understanding protein ubiquitination. Nat Biotechnol. 2003 Aug;21(8):921–926. [PubMed]
  • Liu Z, Haas AL, Diaz LA, Conrad CA, Gíudice GJ. Characterization of a novel keratinocyte ubiquitin carrier protein. J Biol Chem. 1996 Feb 2;271(5):2817–2822. [PubMed]
  • Schnell Joshua D, Hicke Linda. Non-traditional functions of ubiquitin and ubiquitin-binding proteins. J Biol Chem. 2003 Sep 19;278(38):35857–35860. [PubMed]
  • Hicke L. Protein regulation by monoubiquitin. Nat Rev Mol Cell Biol. 2001 Mar;2(3):195–201. [PubMed]
  • Katzmann David J, Odorizzi Greg, Emr Scott D. Receptor downregulation and multivesicular-body sorting. Nat Rev Mol Cell Biol. 2002 Dec;3(12):893–905. [PubMed]
  • Terrell J, Shih S, Dunn R, Hicke L. A function for monoubiquitination in the internalization of a G protein-coupled receptor. Mol Cell. 1998 Jan;1(2):193–202. [PubMed]
  • Shih SC, Sloper-Mould KE, Hicke L. Monoubiquitin carries a novel internalization signal that is appended to activated receptors. EMBO J. 2000 Jan 17;19(2):187–198. [PMC free article] [PubMed]
  • Nakatsu F, Sakuma M, Matsuo Y, Arase H, Yamasaki S, Nakamura N, Saito T, Ohno H. A Di-leucine signal in the ubiquitin moiety. Possible involvement in ubiquitination-mediated endocytosis. J Biol Chem. 2000 Aug 25;275(34):26213–26219. [PubMed]
  • Haglund Kaisa, Sigismund Sara, Polo Simona, Szymkiewicz Iwona, Di Fiore Pier Paolo, Dikic Ivan. Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. Nat Cell Biol. 2003 May;5(5):461–466. [PubMed]
  • Mosesson Yaron, Shtiegman Keren, Katz Menachem, Zwang Yaara, Vereb Gyorgi, Szollosi Janos, Yarden Yosef. Endocytosis of receptor tyrosine kinases is driven by monoubiquitylation, not polyubiquitylation. J Biol Chem. 2003 Jun 13;278(24):21323–21326. [PubMed]
  • Henry Karl W, Wyce Anastasia, Lo Wan-Sheng, Duggan Laura J, Emre N C Tolga, Kao Cheng-Fu, Pillus Lorraine, Shilatifard Ali, Osley Mary Ann, Berger Shelley L. Transcriptional activation via sequential histone H2B ubiquitylation and deubiquitylation, mediated by SAGA-associated Ubp8. Genes Dev. 2003 Nov 1;17(21):2648–2663. [PMC free article] [PubMed]
  • Galan JM, Haguenauer-Tsapis R. Ubiquitin lys63 is involved in ubiquitination of a yeast plasma membrane protein. EMBO J. 1997 Oct 1;16(19):5847–5854. [PMC free article] [PubMed]
  • Hofmann RM, Pickart CM. Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair. Cell. 1999 Mar 5;96(5):645–653. [PubMed]
  • Deng L, Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C, Chen ZJ. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell. 2000 Oct 13;103(2):351–361. [PubMed]
  • Spence J, Gali RR, Dittmar G, Sherman F, Karin M, Finley D. Cell cycle-regulated modification of the ribosome by a variant multiubiquitin chain. Cell. 2000 Jul 7;102(1):67–76. [PubMed]
  • Hofmann RM, Pickart CM. In vitro assembly and recognition of Lys-63 polyubiquitin chains. J Biol Chem. 2001 Jul 27;276(30):27936–27943. [PubMed]
  • Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature. 2001 Jul 19;412(6844):346–351. [PubMed]
  • Cook WJ, Jeffrey LC, Carson M, Chen Z, Pickart CM. Structure of a diubiquitin conjugate and a model for interaction with ubiquitin conjugating enzyme (E2). J Biol Chem. 1992 Aug 15;267(23):16467–16471. [PubMed]
  • Varadan Ranjani, Walker Olivier, Pickart Cecile, Fushman David. Structural properties of polyubiquitin chains in solution. J Mol Biol. 2002 Dec 6;324(4):637–647. [PubMed]
  • Varadan Ranjani, Assfalg Michael, Haririnia Aydin, Raasi Shahri, Pickart Cecile, Fushman David. Solution conformation of Lys63-linked di-ubiquitin chain provides clues to functional diversity of polyubiquitin signaling. J Biol Chem. 2004 Feb 20;279(8):7055–7063. [PubMed]
  • Lam YA, DeMartino GN, Pickart CM, Cohen RE. Specificity of the ubiquitin isopeptidase in the PA700 regulatory complex of 26 S proteasomes. J Biol Chem. 1997 Nov 7;272(45):28438–28446. [PubMed]
  • Nishikawa Hiroyuki, Ooka Seido, Sato Ko, Arima Kei, Okamoto Joji, Klevit Rachel E, Fukuda Mamoru, Ohta Tomohiko. Mass spectrometric and mutational analyses reveal Lys-6-linked polyubiquitin chains catalyzed by BRCA1-BARD1 ubiquitin ligase. J Biol Chem. 2004 Feb 6;279(6):3916–3924. [PubMed]
  • Wu-Baer Foon, Lagrazon Karen, Yuan Wei, Baer Richard. The BRCA1/BARD1 heterodimer assembles polyubiquitin chains through an unconventional linkage involving lysine residue K6 of ubiquitin. J Biol Chem. 2003 Sep 12;278(37):34743–34746. [PubMed]
  • Hochstrasser M. Evolution and function of ubiquitin-like protein-conjugation systems. Nat Cell Biol. 2000 Aug;2(8):E153–E157. [PubMed]
  • Larsen Christopher N, Wang Hailin. The ubiquitin superfamily: members, features, and phylogenies. J Proteome Res. 2002 Sep-Oct;1(5):411–419. [PubMed]
  • Seeler Jacob-S, Dejean Anne. Nuclear and unclear functions of SUMO. Nat Rev Mol Cell Biol. 2003 Sep;4(9):690–699. [PubMed]
  • Shiio Yuzuru, Eisenman Robert N. Histone sumoylation is associated with transcriptional repression. Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13225–13230. [PMC free article] [PubMed]
  • Matunis MJ, Coutavas E, Blobel G. A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex. J Cell Biol. 1996 Dec;135(6 Pt 1):1457–1470. [PMC free article] [PubMed]
  • Mahajan R, Delphin C, Guan T, Gerace L, Melchior F. A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2. Cell. 1997 Jan 10;88(1):97–107. [PubMed]
  • Joseph Jomon, Tan Shyh-Han, Karpova Tatiana S, McNally James G, Dasso Mary. SUMO-1 targets RanGAP1 to kinetochores and mitotic spindles. J Cell Biol. 2002 Feb 18;156(4):595–602. [PMC free article] [PubMed]
  • Müller S, Matunis MJ, Dejean A. Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus. EMBO J. 1998 Jan 2;17(1):61–70. [PMC free article] [PubMed]
  • Desterro JM, Rodriguez MS, Hay RT. SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation. Mol Cell. 1998 Aug;2(2):233–239. [PubMed]
  • Hoege Carsten, Pfander Boris, Moldovan George-Lucian, Pyrowolakis George, Jentsch Stefan. RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature. 2002 Sep 12;419(6903):135–141. [PubMed]
  • Pickart CM. Mechanisms underlying ubiquitination. Annu Rev Biochem. 2001;70:503–533. [PubMed]
  • Glickman Michael H, Ciechanover Aaron. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev. 2002 Apr;82(2):373–428. [PubMed]
  • Haas AL, Rose IA. The mechanism of ubiquitin activating enzyme. A kinetic and equilibrium analysis. J Biol Chem. 1982 Sep 10;257(17):10329–10337. [PubMed]
  • Haas AL, Warms JV, Hershko A, Rose IA. Ubiquitin-activating enzyme. Mechanism and role in protein-ubiquitin conjugation. J Biol Chem. 1982 Mar 10;257(5):2543–2548. [PubMed]
  • Breitschopf K, Bengal E, Ziv T, Admon A, Ciechanover A. A novel site for ubiquitination: the N-terminal residue, and not internal lysines of MyoD, is essential for conjugation and degradation of the protein. EMBO J. 1998 Oct 15;17(20):5964–5973. [PMC free article] [PubMed]
  • Aviel S, Winberg G, Massucci M, Ciechanover A. Degradation of the epstein-barr virus latent membrane protein 1 (LMP1) by the ubiquitin-proteasome pathway. Targeting via ubiquitination of the N-terminal residue. J Biol Chem. 2000 Aug 4;275(31):23491–23499. [PubMed]
  • Reinstein E, Scheffner M, Oren M, Ciechanover A, Schwartz A. Degradation of the E7 human papillomavirus oncoprotein by the ubiquitin-proteasome system: targeting via ubiquitination of the N-terminal residue. Oncogene. 2000 Nov 30;19(51):5944–5950. [PubMed]
  • Bloom Joanna, Amador Virginia, Bartolini Francesca, DeMartino George, Pagano Michele. Proteasome-mediated degradation of p21 via N-terminal ubiquitinylation. Cell. 2003 Oct 3;115(1):71–82. [PubMed]
  • Laney JD, Hochstrasser M. Substrate targeting in the ubiquitin system. Cell. 1999 May 14;97(4):427–430. [PubMed]
  • Chau V, Tobias JW, Bachmair A, Marriott D, Ecker DJ, Gonda DK, Varshavsky A. A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science. 1989 Mar 24;243(4898):1576–1583. [PubMed]
  • Koegl M, Hoppe T, Schlenker S, Ulrich HD, Mayer TU, Jentsch S. A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly. Cell. 1999 Mar 5;96(5):635–644. [PubMed]
  • Mastrandrea LD, You J, Niles EG, Pickart CM. E2/E3-mediated assembly of lysine 29-linked polyubiquitin chains. J Biol Chem. 1999 Sep 17;274(38):27299–27306. [PubMed]
  • You J, Pickart CM. A HECT domain E3 enzyme assembles novel polyubiquitin chains. J Biol Chem. 2001 Jun 8;276(23):19871–19878. [PubMed]
  • Chung CH, Baek SH. Deubiquitinating enzymes: their diversity and emerging roles. Biochem Biophys Res Commun. 1999 Dec 29;266(3):633–640. [PubMed]
  • Voges D, Zwickl P, Baumeister W. The 26S proteasome: a molecular machine designed for controlled proteolysis. Annu Rev Biochem. 1999;68:1015–1068. [PubMed]
  • Thrower JS, Hoffman L, Rechsteiner M, Pickart CM. Recognition of the polyubiquitin proteolytic signal. EMBO J. 2000 Jan 4;19(1):94–102. [PMC free article] [PubMed]
  • Verma Rati, Aravind L, Oania Robert, McDonald W Hayes, Yates John R, 3rd, Koonin Eugene V, Deshaies Raymond J. Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome. Science. 2002 Oct 18;298(5593):611–615. [PubMed]
  • Petroski Matthew D, Deshaies Raymond J. Context of multiubiquitin chain attachment influences the rate of Sic1 degradation. Mol Cell. 2003 Jun;11(6):1435–1444. [PubMed]
  • Kornitzer D, Raboy B, Kulka RG, Fink GR. Regulated degradation of the transcription factor Gcn4. EMBO J. 1994 Dec 15;13(24):6021–6030. [PMC free article] [PubMed]
  • Nakamura S, Roth JA, Mukhopadhyay T. Multiple lysine mutations in the C-terminal domain of p53 interfere with MDM2-dependent protein degradation and ubiquitination. Mol Cell Biol. 2000 Dec;20(24):9391–9398. [PMC free article] [PubMed]
  • Madura Kiran. The ubiquitin-associated (UBA) domain: on the path from prudence to prurience. Cell Cycle. 2002 Jul-Aug;1(4):235–244. [PubMed]
  • Di Fiore Pier Paolo, Polo Simona, Hofmann Kay. When ubiquitin meets ubiquitin receptors: a signalling connection. Nat Rev Mol Cell Biol. 2003 Jun;4(6):491–497. [PubMed]
  • Ortolan TG, Tongaonkar P, Lambertson D, Chen L, Schauber C, Madura K. The DNA repair protein rad23 is a negative regulator of multi-ubiquitin chain assembly. Nat Cell Biol. 2000 Sep;2(9):601–608. [PubMed]
  • Meyer Hemmo H, Wang Yanzhuang, Warren Graham. Direct binding of ubiquitin conjugates by the mammalian p97 adaptor complexes, p47 and Ufd1-Npl4. EMBO J. 2002 Nov 1;21(21):5645–5652. [PMC free article] [PubMed]
  • Shekhtman Alexander, Cowburn David. A ubiquitin-interacting motif from Hrs binds to and occludes the ubiquitin surface necessary for polyubiquitination in monoubiquitinated proteins. Biochem Biophys Res Commun. 2002 Sep 6;296(5):1222–1227. [PubMed]
  • Kang Richard S, Daniels Cynthia M, Francis Smitha A, Shih Susan C, Salerno William J, Hicke Linda, Radhakrishnan Ishwar. Solution structure of a CUE-ubiquitin complex reveals a conserved mode of ubiquitin binding. Cell. 2003 May 30;113(5):621–630. [PubMed]
  • Ryu Kyoung-Seok, Lee Kyung-Jin, Bae Sung-Hun, Kim Byoung-Kook, Kim Kyoung-Ah, Choi Byong-Seok. Binding surface mapping of intra- and interdomain interactions among hHR23B, ubiquitin, and polyubiquitin binding site 2 of S5a. J Biol Chem. 2003 Sep 19;278(38):36621–36627. [PubMed]
  • Hartmann-Petersen Rasmus, Hendil Klavs B, Gordon Colin. Ubiquitin binding proteins protect ubiquitin conjugates from disassembly. FEBS Lett. 2003 Jan 30;535(1-3):77–81. [PubMed]
  • Raasi Shahri, Pickart Cecile M. Rad23 ubiquitin-associated domains (UBA) inhibit 26 S proteasome-catalyzed proteolysis by sequestering lysine 48-linked polyubiquitin chains. J Biol Chem. 2003 Mar 14;278(11):8951–8959. [PubMed]
  • Kominami K, Okura N, Kawamura M, DeMartino GN, Slaughter CA, Shimbara N, Chung CH, Fujimuro M, Yokosawa H, Shimizu Y, et al. Yeast counterparts of subunits S5a and p58 (S3) of the human 26S proteasome are encoded by two multicopy suppressors of nin1-1. Mol Biol Cell. 1997 Jan;8(1):171–187. [PMC free article] [PubMed]
  • Young P, Deveraux Q, Beal RE, Pickart CM, Rechsteiner M. Characterization of two polyubiquitin binding sites in the 26 S protease subunit 5a. J Biol Chem. 1998 Mar 6;273(10):5461–5467. [PubMed]
  • Funakoshi Minoru, Sasaki Toru, Nishimoto Takeharu, Kobayashi Hideki. Budding yeast Dsk2p is a polyubiquitin-binding protein that can interact with the proteasome. Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):745–750. [PMC free article] [PubMed]
  • Rao Hai, Sastry Ashwani. Recognition of specific ubiquitin conjugates is important for the proteolytic functions of the ubiquitin-associated domain proteins Dsk2 and Rad23. J Biol Chem. 2002 Apr 5;277(14):11691–11695. [PubMed]
  • Kleijnen MF, Shih AH, Zhou P, Kumar S, Soccio RE, Kedersha NL, Gill G, Howley PM. The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome. Mol Cell. 2000 Aug;6(2):409–419. [PubMed]
  • Seeger Michael, Hartmann-Petersen Rasmus, Wilkinson Caroline R M, Wallace Mairi, Samejima Itaru, Taylor Martin S, Gordon Colin. Interaction of the anaphase-promoting complex/cyclosome and proteasome protein complexes with multiubiquitin chain-binding proteins. J Biol Chem. 2003 May 9;278(19):16791–16796. [PubMed]
  • Tongaonkar P, Chen L, Lambertson D, Ko B, Madura K. Evidence for an interaction between ubiquitin-conjugating enzymes and the 26S proteasome. Mol Cell Biol. 2000 Jul;20(13):4691–4698. [PMC free article] [PubMed]
  • Verma R, Chen S, Feldman R, Schieltz D, Yates J, Dohmen J, Deshaies RJ. Proteasomal proteomics: identification of nucleotide-sensitive proteasome-interacting proteins by mass spectrometric analysis of affinity-purified proteasomes. Mol Biol Cell. 2000 Oct;11(10):3425–3439. [PMC free article] [PubMed]
  • Xie Y, Varshavsky A. Physical association of ubiquitin ligases and the 26S proteasome. Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2497–2502. [PMC free article] [PubMed]
  • Davy A, Bello P, Thierry-Mieg N, Vaglio P, Hitti J, Doucette-Stamm L, Thierry-Mieg D, Reboul J, Boulton S, Walhout AJ, et al. A protein-protein interaction map of the Caenorhabditis elegans 26S proteasome. EMBO Rep. 2001 Sep;2(9):821–828. [PMC free article] [PubMed]
  • Hartmann-Petersen Rasmus, Seeger Michael, Gordon Colin. Transferring substrates to the 26S proteasome. Trends Biochem Sci. 2003 Jan;28(1):26–31. [PubMed]
  • Lake MW, Wuebbens MM, Rajagopalan KV, Schindelin H. Mechanism of ubiquitin activation revealed by the structure of a bacterial MoeB-MoaD complex. Nature. 2001 Nov 15;414(6861):325–329. [PubMed]
  • Walden Helen, Podgorski Michael S, Schulman Brenda A. Insights into the ubiquitin transfer cascade from the structure of the activating enzyme for NEDD8. Nature. 2003 Mar 20;422(6929):330–334. [PubMed]
  • Walden Helen, Podgorski Michael S, Huang Danny T, Miller David W, Howard Rebecca J, Minor Daniel L, Jr, Holton James M, Schulman Brenda A. The structure of the APPBP1-UBA3-NEDD8-ATP complex reveals the basis for selective ubiquitin-like protein activation by an E1. Mol Cell. 2003 Dec;12(6):1427–1437. [PubMed]
  • Rajagopalan KV. Biosynthesis and processing of the molybdenum cofactors. Biochem Soc Trans. 1997 Aug;25(3):757–761. [PubMed]
  • Osaka F, Kawasaki H, Aida N, Saeki M, Chiba T, Kawashima S, Tanaka K, Kato S. A new NEDD8-ligating system for cullin-4A. Genes Dev. 1998 Aug 1;12(15):2263–2268. [PMC free article] [PubMed]
  • VanDemark Andrew P, Hill Christopher P. Structural basis of ubiquitylation. Curr Opin Struct Biol. 2002 Dec;12(6):822–830. [PubMed]
  • Huang L, Kinnucan E, Wang G, Beaudenon S, Howley PM, Huibregtse JM, Pavletich NP. Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2-E3 enzyme cascade. Science. 1999 Nov 12;286(5443):1321–1326. [PubMed]
  • Zheng N, Wang P, Jeffrey PD, Pavletich NP. Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-protein ligases. Cell. 2000 Aug 18;102(4):533–539. [PubMed]
  • VanDemark AP, Hofmann RM, Tsui C, Pickart CM, Wolberger C. Molecular insights into polyubiquitin chain assembly: crystal structure of the Mms2/Ubc13 heterodimer. Cell. 2001 Jun 15;105(6):711–720. [PubMed]
  • Bernier-Villamor Victor, Sampson Deborah A, Matunis Michael J, Lima Christopher D. Structural basis for E2-mediated SUMO conjugation revealed by a complex between ubiquitin-conjugating enzyme Ubc9 and RanGAP1. Cell. 2002 Feb 8;108(3):345–356. [PubMed]
  • Miura T, Klaus W, Gsell B, Miyamoto C, Senn H. Characterization of the binding interface between ubiquitin and class I human ubiquitin-conjugating enzyme 2b by multidimensional heteronuclear NMR spectroscopy in solution. J Mol Biol. 1999 Jul 2;290(1):213–228. [PubMed]
  • Hamilton KS, Ellison MJ, Barber KR, Williams RS, Huzil JT, McKenna S, Ptak C, Glover M, Shaw GS. Structure of a conjugating enzyme-ubiquitin thiolester intermediate reveals a novel role for the ubiquitin tail. Structure. 2001 Oct;9(10):897–904. [PubMed]
  • Wu Pei-Ying, Hanlon Mary, Eddins Michael, Tsui Colleen, Rogers Richard S, Jensen Jane P, Matunis Michael J, Weissman Allan M, Weisman Allan M, Weissman Allan M, et al. A conserved catalytic residue in the ubiquitin-conjugating enzyme family. EMBO J. 2003 Oct 1;22(19):5241–5250. [PMC free article] [PubMed]
  • Hu Min, Li Pingwei, Li Muyang, Li Wenyu, Yao Tingting, Wu Jia-Wei, Gu Wei, Cohen Robert E, Shi Yigong. Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde. Cell. 2002 Dec 27;111(7):1041–1054. [PubMed]
  • Huibregtse JM, Scheffner M, Beaudenon S, Howley PM. A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2563–2567. [PMC free article] [PubMed]
  • Scheffner M, Nuber U, Huibregtse JM. Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade. Nature. 1995 Jan 5;373(6509):81–83. [PubMed]
  • Schwarz SE, Rosa JL, Scheffner M. Characterization of human hect domain family members and their interaction with UbcH5 and UbcH7. J Biol Chem. 1998 May 15;273(20):12148–12154. [PubMed]
  • Verdecia Mark A, Joazeiro Claudio A P, Wells Nicholas J, Ferrer Jean-Luc, Bowman Marianne E, Hunter Tony, Noel Joseph P. Conformational flexibility underlies ubiquitin ligation mediated by the WWP1 HECT domain E3 ligase. Mol Cell. 2003 Jan;11(1):249–259. [PubMed]
  • Zheng Ning. A closer look of the HECTic ubiquitin ligases. Structure. 2003 Jan;11(1):5–6. [PubMed]
  • Deshaies RJ. SCF and Cullin/Ring H2-based ubiquitin ligases. Annu Rev Cell Dev Biol. 1999;15:435–467. [PubMed]
  • Joazeiro CA, Weissman AM. RING finger proteins: mediators of ubiquitin ligase activity. Cell. 2000 Sep 1;102(5):549–552. [PubMed]
  • Hatakeyama Shigetsugu, Nakayama Kei-ichi I. U-box proteins as a new family of ubiquitin ligases. Biochem Biophys Res Commun. 2003 Mar 21;302(4):635–645. [PubMed]
  • Lorick KL, Jensen JP, Fang S, Ong AM, Hatakeyama S, Weissman AM. RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination. Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11364–11369. [PMC free article] [PubMed]
  • Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, et al. Initial sequencing and analysis of the human genome. Nature. 2001 Feb 15;409(6822):860–921. [PubMed]
  • Borden KL. RING domains: master builders of molecular scaffolds? J Mol Biol. 2000 Feb 4;295(5):1103–1112. [PubMed]
  • Ohi Melanie D, Vander Kooi Craig W, Rosenberg Joshua A, Chazin Walter J, Gould Kathleen L. Structural insights into the U-box, a domain associated with multi-ubiquitination. Nat Struct Biol. 2003 Apr;10(4):250–255. [PubMed]
  • Albert Thomas K, Hanzawa Hiroyuki, Legtenberg Yvonne I A, de Ruwe Marjolein J, van den Heuvel Fiona A J, Collart Martine A, Boelens Rolf, Timmers H Th Marc. Identification of a ubiquitin-protein ligase subunit within the CCR4-NOT transcription repressor complex. EMBO J. 2002 Feb 1;21(3):355–364. [PMC free article] [PubMed]
  • Zheng Ning, Schulman Brenda A, Song Langzhou, Miller Julie J, Jeffrey Philip D, Wang Ping, Chu Claire, Koepp Deanna M, Elledge Stephen J, Pagano Michele, et al. Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex. Nature. 2002 Apr 18;416(6882):703–709. [PubMed]
  • Seol JH, Feldman RM, Zachariae W, Shevchenko A, Correll CC, Lyapina S, Chi Y, Galova M, Claypool J, Sandmeyer S, et al. Cdc53/cullin and the essential Hrt1 RING-H2 subunit of SCF define a ubiquitin ligase module that activates the E2 enzyme Cdc34. Genes Dev. 1999 Jun 15;13(12):1614–1626. [PMC free article] [PubMed]
  • Tang Z, Li B, Bharadwaj R, Zhu H, Ozkan E, Hakala K, Deisenhofer J, Yu H. APC2 Cullin protein and APC11 RING protein comprise the minimal ubiquitin ligase module of the anaphase-promoting complex. Mol Biol Cell. 2001 Dec;12(12):3839–3851. [PMC free article] [PubMed]
  • Moraes TF, Edwards RA, McKenna S, Pastushok L, Xiao W, Glover JN, Ellison MJ. Crystal structure of the human ubiquitin conjugating enzyme complex, hMms2-hUbc13. Nat Struct Biol. 2001 Aug;8(8):669–673. [PubMed]
  • Bai C, Sen P, Hofmann K, Ma L, Goebl M, Harper JW, Elledge SJ. SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box. Cell. 1996 Jul 26;86(2):263–274. [PubMed]
  • Feldman RM, Correll CC, Kaplan KB, Deshaies RJ. A complex of Cdc4p, Skp1p, and Cdc53p/cullin catalyzes ubiquitination of the phosphorylated CDK inhibitor Sic1p. Cell. 1997 Oct 17;91(2):221–230. [PubMed]
  • Skowyra D, Craig KL, Tyers M, Elledge SJ, Harper JW. F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex. Cell. 1997 Oct 17;91(2):209–219. [PubMed]
  • Iwai K, Yamanaka K, Kamura T, Minato N, Conaway RC, Conaway JW, Klausner RD, Pause A. Identification of the von Hippel-lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex. Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12436–12441. [PMC free article] [PubMed]
  • Lisztwan J, Imbert G, Wirbelauer C, Gstaiger M, Krek W. The von Hippel-Lindau tumor suppressor protein is a component of an E3 ubiquitin-protein ligase activity. Genes Dev. 1999 Jul 15;13(14):1822–1833. [PMC free article] [PubMed]
  • Kamura T, Burian D, Yan Q, Schmidt SL, Lane WS, Querido E, Branton PE, Shilatifard A, Conaway RC, Conaway JW. Muf1, a novel Elongin BC-interacting leucine-rich repeat protein that can assemble with Cul5 and Rbx1 to reconstitute a ubiquitin ligase. J Biol Chem. 2001 Aug 10;276(32):29748–29753. [PubMed]
  • Kile Benjamin T, Schulman Brenda A, Alexander Warren S, Nicola Nicos A, Martin Helene M E, Hilton Douglas J. The SOCS box: a tale of destruction and degradation. Trends Biochem Sci. 2002 May;27(5):235–241. [PubMed]
  • Ulane Christina M, Horvath Curt M. Paramyxoviruses SV5 and HPIV2 assemble STAT protein ubiquitin ligase complexes from cellular components. Virology. 2002 Dec 20;304(2):160–166. [PubMed]
  • Pintard Lionel, Willis John H, Willems Andrew, Johnson Jacque-Lynne F, Srayko Martin, Kurz Thimo, Glaser Sarah, Mains Paul E, Tyers Mike, Bowerman Bruce, et al. The BTB protein MEL-26 is a substrate-specific adaptor of the CUL-3 ubiquitin-ligase. Nature. 2003 Sep 18;425(6955):311–316. [PubMed]
  • Xu Lai, Wei Yue, Reboul Jerome, Vaglio Philippe, Shin Tae-Ho, Vidal Marc, Elledge Stephen J, Harper J Wade. BTB proteins are substrate-specific adaptors in an SCF-like modular ubiquitin ligase containing CUL-3. Nature. 2003 Sep 18;425(6955):316–321. [PubMed]
  • Geyer Rory, Wee Susan, Anderson Scott, Yates John, Wolf Dieter A. BTB/POZ domain proteins are putative substrate adaptors for cullin 3 ubiquitin ligases. Mol Cell. 2003 Sep;12(3):783–790. [PubMed]
  • Furukawa Manabu, He Yizhou Joseph, Borchers Christoph, Xiong Yue. Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubiquitin ligases. Nat Cell Biol. 2003 Nov;5(11):1001–1007. [PubMed]
  • Higa Leigh Ann A, Mihaylov Ivailo S, Banks Damon P, Zheng Jianyu, Zhang Hui. Radiation-mediated proteolysis of CDT1 by CUL4-ROC1 and CSN complexes constitutes a new checkpoint. Nat Cell Biol. 2003 Nov;5(11):1008–1015. [PubMed]
  • Jackson PK, Eldridge AG, Freed E, Furstenthal L, Hsu JY, Kaiser BK, Reimann JD. The lore of the RINGs: substrate recognition and catalysis by ubiquitin ligases. Trends Cell Biol. 2000 Oct;10(10):429–439. [PubMed]
  • Tyers M, Jorgensen P. Proteolysis and the cell cycle: with this RING I do thee destroy. Curr Opin Genet Dev. 2000 Feb;10(1):54–64. [PubMed]
  • Furukawa Manabu, Ohta Tomohiko, Xiong Yue. Activation of UBC5 ubiquitin-conjugating enzyme by the RING finger of ROC1 and assembly of active ubiquitin ligases by all cullins. J Biol Chem. 2002 May 3;277(18):15758–15765. [PubMed]
  • Harper J Wade, Burton Janet L, Solomon Mark J. The anaphase-promoting complex: it's not just for mitosis any more. Genes Dev. 2002 Sep 1;16(17):2179–2206. [PubMed]
  • Peters Jan-Michael. The anaphase-promoting complex: proteolysis in mitosis and beyond. Mol Cell. 2002 May;9(5):931–943. [PubMed]
  • Yoon Hyun-Joo, Feoktistova Anna, Wolfe Benjamin A, Jennings Jennifer L, Link Andrew J, Gould Kathleen L. Proteomics analysis identifies new components of the fission and budding yeast anaphase-promoting complexes. Curr Biol. 2002 Dec 10;12(23):2048–2054. [PubMed]
  • Hall Mark C, Torres Matthew P, Schroeder Gottfried K, Borchers Christoph H. Mnd2 and Swm1 are core subunits of the Saccharomyces cerevisiae anaphase-promoting complex. J Biol Chem. 2003 May 9;278(19):16698–16705. [PubMed]
  • Passmore Lori A, McCormack Elizabeth A, Au Shannon W N, Paul Angela, Willison Keith R, Harper J Wade, Barford David. Doc1 mediates the activity of the anaphase-promoting complex by contributing to substrate recognition. EMBO J. 2003 Feb 17;22(4):786–796. [PMC free article] [PubMed]
  • Irniger S, Piatti S, Michaelis C, Nasmyth K. Genes involved in sister chromatid separation are needed for B-type cyclin proteolysis in budding yeast. Cell. 1995 Apr 21;81(2):269–278. [PubMed]
  • Zachariae W, Shevchenko A, Andrews PD, Ciosk R, Galova M, Stark MJ, Mann M, Nasmyth K. Mass spectrometric analysis of the anaphase-promoting complex from yeast: identification of a subunit related to cullins. Science. 1998 Feb 20;279(5354):1216–1219. [PubMed]
  • Gieffers C, Dube P, Harris JR, Stark H, Peters JM. Three-dimensional structure of the anaphase-promoting complex. Mol Cell. 2001 Apr;7(4):907–913. [PubMed]
  • Skowyra D, Koepp DM, Kamura T, Conrad MN, Conaway RC, Conaway JW, Elledge SJ, Harper JW. Reconstitution of G1 cyclin ubiquitination with complexes containing SCFGrr1 and Rbx1. Science. 1999 Apr 23;284(5414):662–665. [PubMed]
  • Gmachl M, Gieffers C, Podtelejnikov AV, Mann M, Peters JM. The RING-H2 finger protein APC11 and the E2 enzyme UBC4 are sufficient to ubiquitinate substrates of the anaphase-promoting complex. Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):8973–8978. [PMC free article] [PubMed]
  • Leverson JD, Joazeiro CA, Page AM, Huang H k, Hieter P, Hunter T. The APC11 RING-H2 finger mediates E2-dependent ubiquitination. Mol Biol Cell. 2000 Jul;11(7):2315–2325. [PMC free article] [PubMed]
  • Schulman BA, Carrano AC, Jeffrey PD, Bowen Z, Kinnucan ER, Finnin MS, Elledge SJ, Harper JW, Pagano M, Pavletich NP. Insights into SCF ubiquitin ligases from the structure of the Skp1-Skp2 complex. Nature. 2000 Nov 16;408(6810):381–386. [PubMed]
  • King RW, Glotzer M, Kirschner MW. Mutagenic analysis of the destruction signal of mitotic cyclins and structural characterization of ubiquitinated intermediates. Mol Biol Cell. 1996 Sep;7(9):1343–1357. [PMC free article] [PubMed]
  • Wu Geng, Xu Guozhou, Schulman Brenda A, Jeffrey Philip D, Harper J Wade, Pavletich Nikola P. Structure of a beta-TrCP1-Skp1-beta-catenin complex: destruction motif binding and lysine specificity of the SCF(beta-TrCP1) ubiquitin ligase. Mol Cell. 2003 Jun;11(6):1445–1456. [PubMed]
  • Orlicky Stephen, Tang Xiaojing, Willems Andrew, Tyers Mike, Sicheri Frank. Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase. Cell. 2003 Jan 24;112(2):243–256. [PubMed]
  • McKenna Sean, Moraes Trevor, Pastushok Landon, Ptak Christopher, Xiao Wei, Spyracopoulos Leo, Ellison Michael J. An NMR-based model of the ubiquitin-bound human ubiquitin conjugation complex Mms2.Ubc13. The structural basis for lysine 63 chain catalysis. J Biol Chem. 2003 Apr 11;278(15):13151–13158. [PubMed]
  • Ulrich HD, Jentsch S. Two RING finger proteins mediate cooperation between ubiquitin-conjugating enzymes in DNA repair. EMBO J. 2000 Jul 3;19(13):3388–3397. [PMC free article] [PubMed]
  • Grönroos Eva, Hellman Ulf, Heldin Carl-Henrik, Ericsson Johan. Control of Smad7 stability by competition between acetylation and ubiquitination. Mol Cell. 2002 Sep;10(3):483–493. [PubMed]
  • Ito Akihiro, Kawaguchi Yoshiharu, Lai Chun-Hsiang, Kovacs Jeffrey J, Higashimoto Yuichiro, Appella Ettore, Yao Tso-Pang. MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation. EMBO J. 2002 Nov 15;21(22):6236–6245. [PMC free article] [PubMed]
  • Li Muyang, Luo Jianyuan, Brooks Christopher L, Gu Wei. Acetylation of p53 inhibits its ubiquitination by Mdm2. J Biol Chem. 2002 Dec 27;277(52):50607–50611. [PubMed]
  • Giandomenico Valeria, Simonsson Maria, Grönroos Eva, Ericsson Johan. Coactivator-dependent acetylation stabilizes members of the SREBP family of transcription factors. Mol Cell Biol. 2003 Apr;23(7):2587–2599. [PMC free article] [PubMed]
  • Freiman Richard N, Tjian Robert. Regulating the regulators: lysine modifications make their mark. Cell. 2003 Jan 10;112(1):11–17. [PubMed]
  • Yan Yuan, Harper Sandy, Speicher David W, Marmorstein Ronen. The catalytic mechanism of the ESA1 histone acetyltransferase involves a self-acetylated intermediate. Nat Struct Biol. 2002 Nov;9(11):862–869. [PubMed]
  • Rojas JR, Trievel RC, Zhou J, Mo Y, Li X, Berger SL, Allis CD, Marmorstein R. Structure of Tetrahymena GCN5 bound to coenzyme A and a histone H3 peptide. Nature. 1999 Sep 2;401(6748):93–98. [PubMed]
  • Silver ET, Gwozd TJ, Ptak C, Goebl M, Ellison MJ. A chimeric ubiquitin conjugating enzyme that combines the cell cycle properties of CDC34 (UBC3) and the DNA repair properties of RAD6 (UBC2): implications for the structure, function and evolution of the E2s. EMBO J. 1992 Aug;11(8):3091–3098. [PMC free article] [PubMed]
  • Chen P, Johnson P, Sommer T, Jentsch S, Hochstrasser M. Multiple ubiquitin-conjugating enzymes participate in the in vivo degradation of the yeast MAT alpha 2 repressor. Cell. 1993 Jul 30;74(2):357–369. [PubMed]
  • Gwozd CS, Arnason TG, Cook WJ, Chau V, Ellison MJ. The yeast UBC4 ubiquitin conjugating enzyme monoubiquitinates itself in vivo: evidence for an E2-E2 homointeraction. Biochemistry. 1995 May 16;34(19):6296–6302. [PubMed]
  • Kovalenko OV, Plug AW, Haaf T, Gonda DK, Ashley T, Ward DC, Radding CM, Golub EI. Mammalian ubiquitin-conjugating enzyme Ubc9 interacts with Rad51 recombination protein and localizes in synaptonemal complexes. Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2958–2963. [PMC free article] [PubMed]
  • Wolf DA, McKeon F, Jackson PK. F-box/WD-repeat proteins pop1p and Sud1p/Pop2p form complexes that bind and direct the proteolysis of cdc18p. Curr Biol. 1999 Apr 8;9(7):373–376. [PubMed]
  • Suzuki H, Chiba T, Suzuki T, Fujita T, Ikenoue T, Omata M, Furuichi K, Shikama H, Tanaka K. Homodimer of two F-box proteins betaTrCP1 or betaTrCP2 binds to IkappaBalpha for signal-dependent ubiquitination. J Biol Chem. 2000 Jan 28;275(4):2877–2884. [PubMed]
  • Hatakeyama S, Jensen JP, Weissman AM. Subcellular localization and ubiquitin-conjugating enzyme (E2) interactions of mammalian HECT family ubiquitin protein ligases. J Biol Chem. 1997 Jun 13;272(24):15085–15092. [PubMed]
  • Ptak C, Prendergast JA, Hodgins R, Kay CM, Chau V, Ellison MJ. Functional and physical characterization of the cell cycle ubiquitin-conjugating enzyme CDC34 (UBC3). Identification of a functional determinant within the tail that facilitates CDC34 self-association. J Biol Chem. 1994 Oct 21;269(42):26539–26545. [PubMed]
  • Varelas Xaralabos, Ptak Christopher, Ellison Michael J. Cdc34 self-association is facilitated by ubiquitin thiolester formation and is required for its catalytic activity. Mol Cell Biol. 2003 Aug;23(15):5388–5400. [PMC free article] [PubMed]
  • Deffenbaugh Andrew E, Scaglione K Matthew, Zhang Lingxiao, Moore Johnnie M, Buranda Tione, Sklar Larry A, Skowyra Dorota. Release of ubiquitin-charged Cdc34-S - Ub from the RING domain is essential for ubiquitination of the SCF(Cdc4)-bound substrate Sic1. Cell. 2003 Sep 5;114(5):611–622. [PubMed]
  • Grossman Steven R, Deato Maria E, Brignone Chrystelle, Chan Ho Man, Kung Andrew L, Tagami Hideaki, Nakatani Yoshihiro, Livingston David M. Polyubiquitination of p53 by a ubiquitin ligase activity of p300. Science. 2003 Apr 11;300(5617):342–344. [PubMed]
  • Li Xiaoming, Yang Yili, Ashwell Jonathan D. TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2. Nature. 2002 Mar 21;416(6878):345–347. [PubMed]

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