Protein ubiquitination (Homo sapiens)

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1, 4-6, 8...3, 7, 25, 313, 13, 14, 22, 313, 13, 22, 313, 25, 313, 7, 13, 14, 313, 13, 14, 22, 313, 13, 22, 3110, 333, 13, 14, 22, 312, 1010, 332, 103, 13, 22, 25, 313, 25, 317, 13, 313, 25, 31cytosolnucleoplasmadenylatedG76-UBC(1-76) UBA1:ubiquitinadenylateUBC(153-228) UBC(457-532) Ub-C114-UBE2C UBC(533-608) adenylatedG152-UBC(77-152) UBA6 CDC34 adenylatedG608-UBC(533-608) adenylatedG380-UBC(305-380) UBE2D1 UBA1UBC(77-152) adenylatedG304-UBC(229-304) Ub-C131-UBE2E1 adenylatedG456-UBC(381-456) UBC(229-304) UBA1UBB(153-228) Ub-C89-UBE2G2 adenylatedG304-UBC(229-304) adenylatedG456-UBC(381-456) Ub-C188-UBE2Z UBC(77-152) UBC(457-532) adenylatedG228-UBB(153-228) RPS27A(1-76) UBC(305-380) UBA1 USP7 UBE2T OTULIN,USP5UBC(229-304) RPS27A(77-156)UBE2K UBB(153-228) UBC(533-608) UBB(77-152)adenylatedlG76-RPS27A(1-76) UBC(153-228) UBA1 UBC(457-532) adenylatedG228-UBC(153-228) Ub-C304-UBE2Q2 UBA1 adenylatedG532-UBC(457-532) RPS27A(1-76) UBE2E1 adenylatedG152-UBB(77-152) adenylatedG152-UBC(77-152) UBB(1-76) adenylatedG380-UBC(305-380) UBC(609-684) UBC(1-76) UCHL3,USP7,USP9XRPS27A(1-76) UBE2A UBB(153-228) UBC(457-532) UBC(153-228) UBA6 RPL40Ub-C90-UBE2G1 UBE2R2 adenylatedG76-UBC(1-76) adenylatedG152-UBB(77-152) ATPUBC(381-456) UBC(381-456) adenylatedG684-UBC(609-684) adenylatedG228-UBC(153-228) adenylatedG228-UBB(153-228) UBC(609-684) adenylatedG76-UBA52(1-76) Ub-C95-UBE2S AMPadenylatedG380-UBC(305-380) UBC(381-456)adenylatedlG76-RPS27A(1-76) UBA1 UBC(533-608) UBB(153-228)UBC(77-152) CDC34 UBC(229-304) UBC(1-76) UBE2G2 UBC(305-380) UBA6 UBE2S UBC(305-380) UBC(1-76) AMPadenylatedG76-UBB(1-76) adenylatedG76-UBA52(1-76) UBC(381-456) UBB(1-76) UBE2W UBB(153-228) UBC(153-228) adenylatedG76-UBC(1-76) UBC(229-304)ATPUBC(533-608) UBC(381-456) UBC(1-76) UBC(77-152) UBB(77-152) Ub-C87-UBE2H adenylatedG152-UBC(77-152) adenylatedG684-UBC(609-684) UBA6:ubiquitinadenylateUb-Cys625-UBA6UBC(305-380)UBC(457-532) E3 ubiquitin ligasesubiquitinate targetproteinsadenylatedG608-UBC(533-608) UBC(1-76) UBA6adenylatedG228-UBC(153-228) Ub-C95-UBE2S adenylatedG304-UBC(229-304) UBC(609-684) UBC(77-152) Ub-C85-UBE2D2 ATPUCHL3 UBC(457-532) UBC(305-380) adenylatedG532-UBC(457-532) UbUBC(77-152) UbadenylatedG228-UBC(153-228) PPiUBB(153-228) UBC(457-532) UBC(305-380) UBC(229-304) UBC(77-152) UBC(533-608) USP9X Ub-C93-UBE2R2 adenylatedG684-UBC(609-684) adenylatedG228-UBB(153-228) Ub:E2 (UBA1substrate)UBE2S UBE2E3 UBC(609-684) adenylatedG76-UBA52(1-76) UBB(77-152) UBC(381-456) UBA52(1-76) UBC(229-304) adenylatedG76-UBA52(1-76) UBE2C adenylatedG684-UBC(609-684) UBC(1-76) adenylatedG76-UBB(1-76) adenylatedG608-UBC(533-608) Ub-Cys632-UBA1adenylatedG456-UBC(381-456) UBE2L3 PPiadenosine5'-monophosphateUBC(229-304) UBB(153-228) adenylatedG76-UBB(1-76) adenylatedG152-UBC(77-152) UBA1 UBB(1-76) UBB(77-152) UBB(153-228) UBC(305-380) UBA52(1-76) adenylatedlG76-RPS27A(1-76) adenylatedG608-UBC(533-608) UBE2G1 UBE2Q2 UBA52(1-76) UBB(77-152) UBC(229-304) UBC(457-532)adenylatedG532-UBC(457-532) adenylatedG380-UBC(305-380) E2 ubiquitinconjugating enzyme(UBA6 substrate)adenylatedG152-UBC(77-152) UBC(609-684)UBE2B PPiUSP5 UBE2Z adenylatedlG76-RPS27A(1-76) adenylatedG304-UBC(229-304) UBC(381-456) UBA52(1-76) UBC(153-228) UBC(229-304) UBC(153-228) UBB(1-76) UBB(1-76) RPS27A(1-76) UBC(229-304) UBC(305-380) Ub-C89-UBE2G2 UBC(533-608) adenylatedG228-UBB(153-228) Ub:E2 (UBA6substrate)adenylatedG152-UBB(77-152) UBC(609-684) Ub-Cys625-UBA6:ubiquitin adenylateUb:E2 (UBA1substrate)Ub-C88-UBE2B UBC(305-380) UBC(305-380) UBC(457-532) Ub-C93-CDC34 adenylatedG380-UBC(305-380) adenylatedG152-UBB(77-152) UBC(533-608) UBA52(1-76)Ub-C91-UBE2W adenylatedG152-UBB(77-152) UBB(153-228) UBE2D2 UBA52(1-76) UBE2L3 adenylatedG76-UBB(1-76) UBB(153-228) adenylatedG380-UBC(305-380) ATPUBC(457-532) UBC(77-152) adenylatedG684-UBC(609-684) UBB(77-152) adenylatedG684-UBC(609-684) adenylatedG76-UBB(1-76) UBA52(1-76) UBC(153-228) UBA52(1-76) adenylatedG532-UBC(457-532) adenylatedG532-UBC(457-532) ATPUBC(533-608) adenylatedG608-UBC(533-608) Ub-C93-CDC34 adenylatedG228-UBB(153-228) UBC(305-380) adenylatedG76-UBA52(1-76) UBC(1-76) UBB(153-228) UBC(77-152) E2 ubiquitinconjugating enzyme(UBA1 substrate)UBE2C adenylatedG152-UBC(77-152) UBA52(1-76) adenylatedG608-UBC(533-608) ATPUBC(381-456) UBB(1-76) UBC(77-152) adenylatedlG76-RPS27A(1-76) adenylatedG456-UBC(381-456) Ub-Cys632-UBA1:ubiquitin adenylateUBC(609-684) RPS27AUBC(381-456) PPiUBC(77-152) Ub-C95-UBE2S UBB(77-152) RPS27A(1-76) UBC(1-76) E2 ubiquitinconjugating enzyme(UBA1 substrate)Ub-C88-UBE2A Ub-C145-UBE2E3 UBC(381-456) UBE2E3 UBE2E3 UBC(609-684) UBC(609-684) adenylatedG532-UBC(457-532) Ub-C85-UBE2D2 UBC(381-456) UBC(381-456) UBC(457-532) UBB(153-228) UBC(533-608)UBA52(1-76) UBB(77-152) adenylatedG228-UBB(153-228) UBB(77-152) UBC(153-228) Ub-C86-UBE2L3 UBC(1-76) Ub-C85-UBE2D2 adenylatedG76-UBC(1-76) UBC(153-228)UBB(77-152) UBC(1-76)UBB(77-152) Ub-C114-UBE2C UBC(153-228) adenylatedG456-UBC(381-456) UBC(153-228) UBA1 UBC(229-304) Ub-C145-UBE2E3 adenylatedG304-UBC(229-304) UBB(1-76)adenylatedlG76-RPS27A(1-76) UBE2G2 RPS27A(1-76) UBE2S UBB(1-76) UBE2D2 adenylatedG304-UBC(229-304) Ub-C85-UBE2D1 RPS27A(1-76)UBB(1-76) UBC(609-684) Ub-C86-UBE2T UBBUBC(153-228) UBC(229-304) Ub-C86-UBE2L3 Ub-C145-UBE2E3 UBB(77-152) adenylatedG152-UBB(77-152) Ub-C86-UBE2L3 adenylatedG228-UBC(153-228) UBE2H adenylatedG76-UBC(1-76) UBB(1-76) RPS27A(1-76) RPS27A(1-76) UBA52(1-76) RPS27A(1-76) OTULIN UBC(1-76) UBC(457-532) UBE2L3 UBC(609-684) Ub-C92-UBE2K UBC(609-684) UBC(533-608) Ub-Cys632-UBA1adenylatedG76-UBC(1-76) UBCUBC(1-76) UBA52(1-76) Ub-Cys632-UBA1:ubiquitin adenylateUBC(305-380) UBB(1-76) PPiadenylatedG456-UBC(381-456) UBC(533-608) RPS27A(1-76) UBA52(1-128)adenylatedG76-UBB(1-76) Ub-C85-UBE2D1 UBB(1-76) adenylatedG228-UBC(153-228) UBE2D2 UBA1:ubiquitinadenylateadenylatedG76-UBA52(1-76) UBE2D1 PPiUBC(77-152)UBC(533-608) RPS27A(1-76) 312614, 26312614, 2614, 2614, 2614, 2626312614, 261714, 26101, 5, 9, 11, 15...1014, 26


Description

Ubiquitin is a small, 76 amino acid residue protein that is conjugated by E3 ubiquitin ligases to other proteins in order to regulate their function or degradation (enzymatic cascade reviewed in Neutzner and Neutzner 2012, Kleiger and Mayor 2014, structures and mechanisms of conjugating enzymes reviewed in Lorenz et al. 2013). Ubiquitination of target proteins usually occurs between the C-terminal glycine residue of ubiquitin and a lysine residue of the target, although linkages with cysteine, serine, and threonine residues are also observed (reviewed in Wang et al. 2012, McDowell and Philpott 2013).
Ubiquitin must first be processed from larger precursors and then activated by formation of a thiol ester bond between ubiquitin and an E1 activating enzyme (UBA1 or UBA6) and transfer to an E2 conjugating enzyme before being transferred by an E3 ligase to a target protein. Precursor proteins containing multiple ubiquitin monomers (polyubiquitins) are produced from the UBB and UBC genes; precursors containing a single ubiquitin monomer and a ribosomal protein are produced from the UBA52 and RPS27A genes. Many proteases (deubiquitinases) may potentially process these precursors yielding monomeric ubiquitin. The proteases OTULIN and USP5 are particularly active in cleaving the polyubiquitin precursors, whereas the proteases UCHL3, USP7, and USP9X cleave the ubiquitin-ribosomal protein precursors yielding ubiquitin monomers (Grou et al. 2015). A resultant ubiquitin monomer is activated by adenylation of the C-terminal glycine followed by conjugation of the C-terminus to a cysteine residue of the E1 enzymes UBA1 or UBA6 via a thiol ester bond. The ubiquitin is then transferred from the E1 enzyme to a cysteine residue of one of several E2 enzymes (reviewed in van Wijk and Timmers 2010, Stewart et al. 2016). Through a less well characterized mechanism, E3 ubiquitin ligases then bring a target protein and the E2-ubiquitin conjugate into proximity so that the ubiquitin is transferred via formation of an amide bond to a particular lysine residue (or, in rarer cases, a thiol ester bond to a cysteine residue or an ester bond to a serine or threonine residue) of the target protein (reviewed in Berndsen and Wolberger 2014). Based on protein homologies, families of E3 ubiquitin ligases have been identified that include RING-type ligases (reviewed in Deshaies et al. 2009, Metzger et al. 2012, Metzger et al. 2014), HECT-type ligases (reviewed in Rotin et al. 2009, Metzger et al. 2012), and RBR-type ligases (reviewed in Dove et al. 2016). A subset of the RING-type ligases participate in CULLIN-RING ligase complexes (CRLs which include SCF complexes, reviewed in Lee and Zhou 2007, Genschik et al. 2013, Skaar et al. 2013, Lee et al. 2014).
Some E3-E2 combinations catalyze mono-ubiquitination of the target protein (reviewed in Nakagawa and Nakayama 2015). Other E3-E2 combinations catalyze conjugation of further ubiquitin monomers to the initial ubiquitin, forming polyubiquitin chains. (It may also be possible for some E3-E2 combinations to preassemble polyubiquitin and transfer it as a unit to the target protein.) Ubiquitin contains several lysine (K) residues and a free alpha amino group to which further ubiquitin can be conjugated. Thus different types of polyubiquitin are possible: K11 linked polyubiquitin is observed in endoplasmic reticulum-associated degradation (ERAD), K29 linked polyubiquitin is observed in lysosomal degradation, K48 linked polyubiquitin directs target proteins to the proteasome for degradation, whereas K63 linked polyubiquitin generally acts as a scaffold to recruit other proteins in several cellular processes, notably DNA repair (reviewed in Komander et al. 2009). Ubiquitination is highly regulated (reviewed in Vittal et al. 2015) and affects all cellular processes including DNA damage response (reviewed in Brown and Jackson 2015), immune signaling (reviewed in Park et al. 2014, Lutz-Nicoladoni et al. 2015), and regulation of normal and cancerous cell growth (reviewed in Skaar and Pagano 2009, Yerlikaya and Yontem 2013, Strikoudis et al. 2014). View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 8852135
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: May, Bruce

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Bibliography

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  1. Dove KK, Stieglitz B, Duncan ED, Rittinger K, Klevit RE.; ''Molecular insights into RBR E3 ligase ubiquitin transfer mechanisms.''; PubMed Europe PMC
  2. Larsen CN, Krantz BA, Wilkinson KD.; ''Substrate specificity of deubiquitinating enzymes: ubiquitin C-terminal hydrolases.''; PubMed Europe PMC
  3. Groettrup M, Pelzer C, Schmidtke G, Hofmann K.; ''Activating the ubiquitin family: UBA6 challenges the field.''; PubMed Europe PMC
  4. Yerlikaya A, Yöntem M.; ''The significance of ubiquitin proteasome pathway in cancer development.''; PubMed Europe PMC
  5. Skaar JR, Pagan JK, Pagano M.; ''Mechanisms and function of substrate recruitment by F-box proteins.''; PubMed Europe PMC
  6. van Wijk SJ, Timmers HT.; ''The family of ubiquitin-conjugating enzymes (E2s): deciding between life and death of proteins.''; PubMed Europe PMC
  7. Eletr ZM, Huang DT, Duda DM, Schulman BA, Kuhlman B.; ''E2 conjugating enzymes must disengage from their E1 enzymes before E3-dependent ubiquitin and ubiquitin-like transfer.''; PubMed Europe PMC
  8. Wang X, Herr RA, Hansen TH.; ''Ubiquitination of substrates by esterification.''; PubMed Europe PMC
  9. McDowell GS, Philpott A.; ''Non-canonical ubiquitylation: mechanisms and consequences.''; PubMed Europe PMC
  10. Grou CP, Pinto MP, Mendes AV, Domingues P, Azevedo JE.; ''The de novo synthesis of ubiquitin: identification of deubiquitinases acting on ubiquitin precursors.''; PubMed Europe PMC
  11. Berndsen CE, Wolberger C.; ''New insights into ubiquitin E3 ligase mechanism.''; PubMed Europe PMC
  12. Lutz-Nicoladoni C, Wolf D, Sopper S.; ''Modulation of Immune Cell Functions by the E3 Ligase Cbl-b.''; PubMed Europe PMC
  13. Hershko A, Heller H, Elias S, Ciechanover A.; ''Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown.''; PubMed Europe PMC
  14. Grenfell SJ, Trausch-Azar JS, Handley-Gearhart PM, Ciechanover A, Schwartz AL.; ''Nuclear localization of the ubiquitin-activating enzyme, E1, is cell-cycle-dependent.''; PubMed Europe PMC
  15. Lee J, Zhou P.; ''DCAFs, the missing link of the CUL4-DDB1 ubiquitin ligase.''; PubMed Europe PMC
  16. Lee EK, Diehl JA.; ''SCFs in the new millennium.''; PubMed Europe PMC
  17. Khoronenkova SV, Dianova II, Ternette N, Kessler BM, Parsons JL, Dianov GL.; ''ATM-dependent downregulation of USP7/HAUSP by PPM1G activates p53 response to DNA damage.''; PubMed Europe PMC
  18. Metzger MB, Hristova VA, Weissman AM.; ''HECT and RING finger families of E3 ubiquitin ligases at a glance.''; PubMed Europe PMC
  19. Park Y, Jin HS, Aki D, Lee J, Liu YC.; ''The ubiquitin system in immune regulation.''; PubMed Europe PMC
  20. Rotin D, Kumar S.; ''Physiological functions of the HECT family of ubiquitin ligases.''; PubMed Europe PMC
  21. Neutzner M, Neutzner A.; ''Enzymes of ubiquitination and deubiquitination.''; PubMed Europe PMC
  22. Haas AL, Warms JV, Hershko A, Rose IA.; ''Ubiquitin-activating enzyme. Mechanism and role in protein-ubiquitin conjugation.''; PubMed Europe PMC
  23. Nakagawa T, Nakayama K.; ''Protein monoubiquitylation: targets and diverse functions.''; PubMed Europe PMC
  24. Skaar JR, Pagano M.; ''Control of cell growth by the SCF and APC/C ubiquitin ligases.''; PubMed Europe PMC
  25. Pelzer C, Kassner I, Matentzoglu K, Singh RK, Wollscheid HP, Scheffner M, Schmidtke G, Groettrup M.; ''UBE1L2, a novel E1 enzyme specific for ubiquitin.''; PubMed Europe PMC
  26. Lee PC, Sowa ME, Gygi SP, Harper JW.; ''Alternative ubiquitin activation/conjugation cascades interact with N-end rule ubiquitin ligases to control degradation of RGS proteins.''; PubMed Europe PMC
  27. Genschik P, Sumara I, Lechner E.; ''The emerging family of CULLIN3-RING ubiquitin ligases (CRL3s): cellular functions and disease implications.''; PubMed Europe PMC
  28. Komander D.; ''The emerging complexity of protein ubiquitination.''; PubMed Europe PMC
  29. Lorenz S, Cantor AJ, Rape M, Kuriyan J.; ''Macromolecular juggling by ubiquitylation enzymes.''; PubMed Europe PMC
  30. Brown JS, Jackson SP.; ''Ubiquitylation, neddylation and the DNA damage response.''; PubMed Europe PMC
  31. Jin J, Li X, Gygi SP, Harper JW.; ''Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging.''; PubMed Europe PMC
  32. Deshaies RJ, Joazeiro CA.; ''RING domain E3 ubiquitin ligases.''; PubMed Europe PMC
  33. Falquet L, Paquet N, Frutiger S, Hughes GJ, Hoang-Van K, Jaton JC.; ''A human de-ubiquitinating enzyme with both isopeptidase and peptidase activities in vitro.''; PubMed Europe PMC
  34. Kleiger G, Mayor T.; ''Perilous journey: a tour of the ubiquitin-proteasome system.''; PubMed Europe PMC
  35. Stewart MD, Ritterhoff T, Klevit RE, Brzovic PS.; ''E2 enzymes: more than just middle men.''; PubMed Europe PMC
  36. Strikoudis A, Guillamot M, Aifantis I.; ''Regulation of stem cell function by protein ubiquitylation.''; PubMed Europe PMC
  37. Vittal V, Stewart MD, Brzovic PS, Klevit RE.; ''Regulating the Regulators: Recent Revelations in the Control of E3 Ubiquitin Ligases.''; PubMed Europe PMC
  38. Metzger MB, Pruneda JN, Klevit RE, Weissman AM.; ''RING-type E3 ligases: master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination.''; PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
101603view11:47, 1 November 2018ReactomeTeamreactome version 66
101139view21:32, 31 October 2018ReactomeTeamreactome version 65
100667view20:06, 31 October 2018ReactomeTeamreactome version 64
100217view16:51, 31 October 2018ReactomeTeamreactome version 63
99768view15:17, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99327view12:47, 31 October 2018ReactomeTeamreactome version 62
93642view11:29, 9 August 2017ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
AMPMetaboliteCHEBI:16027 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
CDC34 ProteinP49427 (Uniprot-TrEMBL)
E2 ubiquitin

conjugating enzyme

(UBA1 substrate)
ComplexR-HSA-8852103 (Reactome)
E2 ubiquitin

conjugating enzyme

(UBA1 substrate)
ComplexR-HSA-8852109 (Reactome)
E2 ubiquitin

conjugating enzyme

(UBA6 substrate)
ComplexR-HSA-8852061 (Reactome)
E3 ubiquitin ligases

ubiquitinate target

proteins
PathwayR-HSA-8866654 (Reactome) E3 ubiquitin ligases catalyze the transfer of an ubiquitin from an E2-ubiquitin conjugate to a target protein. Generally, ubiquitin is transferred via formation of an amide bond to a particular lysine residue of the target protein, but ubiquitylation of cysteine, serine and threonine residues in a few targeted proteins has also been demonstrated (reviewed in McDowell and Philpott 2013, Berndsen and Wolberger 2014). Based on protein homologies, families of E3 ubiquitin ligases have been identified that include RING-type ligases (reviewed in Deshaies et al. 2009, Metzger et al. 2012, Metzger et al. 2014), HECT-type ligases (reviewed in Rotin et al. 2009, Metzger et al. 2012), and RBR-type ligases (reviewed in Dove et al. 2016). A subset of the RING-type ligases participate in CULLIN-RING ligase complexes (CRLs which include SCF complexes, reviewed in Lee and Zhou 2007, Genschik et al. 2013, Skaar et al. 2013, Lee et al. 2014).
Some E3-E2 combinations catalyze mono-ubiquitination of the target protein (reviewed in Nakagawa and Nakayama 2015). Other E3-E2 combinations catalyze conjugation of further ubiquitin monomers to the initial ubiquitin, forming polyubiquitin chains. (It may also be possible for some E3-E2 combinations to preassemble polyubiquitin and transfer it as a unit to the target protein.) Ubiquitin contains several lysine (K) residues and a free alpha amino group to which further ubiquitin can be conjugated. Thus different types of polyubiquitin are possible: K11 linked polyubiquitin is observed in endoplasmic reticulum-associated degradation (ERAD), K29 linked polyubiquitin is observed in lysosomal degradation, K48 linked polyubiquitin directs target proteins to the proteasome for degradation, whereas K63 linked polyubiquitin generally acts as a scaffold to recruit other proteins in several cellular processes, notably DNA repair (reviewed in Komander et al. 2009).
OTULIN ProteinQ96BN8 (Uniprot-TrEMBL)
OTULIN,USP5ComplexR-HSA-8853527 (Reactome)
PPiMetaboliteCHEBI:29888 (ChEBI)
RPL40ProteinP62987 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
RPS27A(1-76)ProteinP62979 (Uniprot-TrEMBL)
RPS27A(77-156)ProteinP62979 (Uniprot-TrEMBL)
RPS27AProteinP62979 (Uniprot-TrEMBL)
UBA1 ProteinP22314 (Uniprot-TrEMBL)
UBA1:ubiquitin adenylateComplexR-HSA-8852055 (Reactome)
UBA1:ubiquitin adenylateComplexR-HSA-8852068 (Reactome)
UBA1ProteinP22314 (Uniprot-TrEMBL)
UBA52(1-128)ProteinP62987 (Uniprot-TrEMBL)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBA52(1-76)ProteinP62987 (Uniprot-TrEMBL)
UBA6 ProteinA0AVT1 (Uniprot-TrEMBL)
UBA6:ubiquitin adenylateComplexR-HSA-8852088 (Reactome)
UBA6ProteinA0AVT1 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(1-76)ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228)ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152)ProteinP0CG47 (Uniprot-TrEMBL)
UBBProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(1-76)ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228)ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304)ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380)ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456)ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532)ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608)ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684)ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152)ProteinP0CG48 (Uniprot-TrEMBL)
UBCProteinP0CG48 (Uniprot-TrEMBL)
UBE2A ProteinP49459 (Uniprot-TrEMBL)
UBE2B ProteinP63146 (Uniprot-TrEMBL)
UBE2C ProteinO00762 (Uniprot-TrEMBL)
UBE2D1 ProteinP51668 (Uniprot-TrEMBL)
UBE2D2 ProteinP62837 (Uniprot-TrEMBL)
UBE2E1 ProteinP51965 (Uniprot-TrEMBL)
UBE2E3 ProteinQ969T4 (Uniprot-TrEMBL)
UBE2G1 ProteinP62253 (Uniprot-TrEMBL)
UBE2G2 ProteinP60604 (Uniprot-TrEMBL)
UBE2H ProteinP62256 (Uniprot-TrEMBL)
UBE2K ProteinP61086 (Uniprot-TrEMBL)
UBE2L3 ProteinP68036 (Uniprot-TrEMBL)
UBE2Q2 ProteinQ8WVN8 (Uniprot-TrEMBL)
UBE2R2 ProteinQ712K3 (Uniprot-TrEMBL)
UBE2S ProteinQ16763 (Uniprot-TrEMBL)
UBE2T ProteinQ9NPD8 (Uniprot-TrEMBL)
UBE2W ProteinQ96B02 (Uniprot-TrEMBL)
UBE2Z ProteinQ9H832 (Uniprot-TrEMBL)
UCHL3 ProteinP15374 (Uniprot-TrEMBL)
UCHL3,USP7,USP9XComplexR-HSA-8853523 (Reactome)
USP5 ProteinP45974 (Uniprot-TrEMBL)
USP7 ProteinQ93009 (Uniprot-TrEMBL)
USP9X ProteinQ93008 (Uniprot-TrEMBL)
Ub-C114-UBE2C ProteinO00762 (Uniprot-TrEMBL)
Ub-C131-UBE2E1 ProteinP51965 (Uniprot-TrEMBL)
Ub-C145-UBE2E3 ProteinQ969T4 (Uniprot-TrEMBL)
Ub-C188-UBE2Z ProteinQ9H832 (Uniprot-TrEMBL)
Ub-C304-UBE2Q2 ProteinQ8WVN8 (Uniprot-TrEMBL)
Ub-C85-UBE2D1 ProteinP51668 (Uniprot-TrEMBL)
Ub-C85-UBE2D2 ProteinP62837 (Uniprot-TrEMBL)
Ub-C86-UBE2L3 ProteinP68036 (Uniprot-TrEMBL)
Ub-C86-UBE2T ProteinQ9NPD8 (Uniprot-TrEMBL)
Ub-C87-UBE2H ProteinP62256 (Uniprot-TrEMBL)
Ub-C88-UBE2A ProteinP49459 (Uniprot-TrEMBL)
Ub-C88-UBE2B ProteinP63146 (Uniprot-TrEMBL)
Ub-C89-UBE2G2 ProteinP60604 (Uniprot-TrEMBL)
Ub-C90-UBE2G1 ProteinP62253 (Uniprot-TrEMBL)
Ub-C91-UBE2W ProteinQ96B02 (Uniprot-TrEMBL)
Ub-C92-UBE2K ProteinP61086 (Uniprot-TrEMBL)
Ub-C93-CDC34 ProteinP49427 (Uniprot-TrEMBL)
Ub-C93-UBE2R2 ProteinQ712K3 (Uniprot-TrEMBL)
Ub-C95-UBE2S ProteinQ16763 (Uniprot-TrEMBL)
Ub-Cys625-UBA6:ubiquitin adenylateComplexR-HSA-8852097 (Reactome)
Ub-Cys625-UBA6ComplexR-HSA-8852066 (Reactome)
Ub-Cys632-UBA1:ubiquitin adenylateComplexR-HSA-8852059 (Reactome)
Ub-Cys632-UBA1:ubiquitin adenylateComplexR-HSA-8852079 (Reactome)
Ub-Cys632-UBA1ComplexR-HSA-8852063 (Reactome)
Ub-Cys632-UBA1ComplexR-HSA-8852095 (Reactome)
Ub:E2 (UBA1 substrate)ComplexR-HSA-8852251 (Reactome)
Ub:E2 (UBA1 substrate)ComplexR-HSA-8864169 (Reactome)
Ub:E2 (UBA6 substrate)ComplexR-HSA-8864229 (Reactome)
UbComplexR-HSA-113595 (Reactome)
UbComplexR-HSA-68524 (Reactome)
adenosine 5'-monophosphateMetaboliteCHEBI:16027 (ChEBI)
adenylatedG152-UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
adenylatedG152-UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
adenylatedG228-UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
adenylatedG228-UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
adenylatedG304-UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
adenylatedG380-UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
adenylatedG456-UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
adenylatedG532-UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
adenylatedG608-UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
adenylatedG684-UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
adenylatedG76-UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
adenylatedG76-UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
adenylatedG76-UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
adenylatedlG76-RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
AMPArrowR-HSA-8852133 (Reactome)
AMPArrowR-HSA-8865098 (Reactome)
ATPR-HSA-8852128 (Reactome)
ATPR-HSA-8852131 (Reactome)
ATPR-HSA-8852132 (Reactome)
ATPR-HSA-8852134 (Reactome)
ATPR-HSA-8865050 (Reactome)
ATPR-HSA-8865090 (Reactome)
E2 ubiquitin

conjugating enzyme

(UBA1 substrate)
R-HSA-8852129 (Reactome)
E2 ubiquitin

conjugating enzyme

(UBA1 substrate)
R-HSA-8852130 (Reactome)
E2 ubiquitin

conjugating enzyme

(UBA6 substrate)
R-HSA-8852127 (Reactome)
OTULIN,USP5mim-catalysisR-HSA-8853515 (Reactome)
OTULIN,USP5mim-catalysisR-HSA-8853529 (Reactome)
PPiArrowR-HSA-8852128 (Reactome)
PPiArrowR-HSA-8852131 (Reactome)
PPiArrowR-HSA-8852132 (Reactome)
PPiArrowR-HSA-8852134 (Reactome)
PPiArrowR-HSA-8865050 (Reactome)
PPiArrowR-HSA-8865090 (Reactome)
R-HSA-8852127 (Reactome) In the cytosol, the UBA6-ubiquitin thiol ester conjugate transfers ubiquitin from UBA6 to an internal cysteine residue of the E2 enzyme, forming a thiol ester conjugate between ubiquitin and the cysteine residue of E2 (Jin et al. 2007, inferred from the rabbit homologue in Hershko et al. 1983, reviewed in Groettrup et al. 2008). As inferred from UBA1, the E2 then disengages from UBA6 (Eletr et al. 2005).
R-HSA-8852128 (Reactome) UBA1 is present in both the cytosol and nucleoplasm (Grenfell et al. 1994). Activation of ubiquitin by UBA1 proceeds through 3 steps: adenylation of ubiquitin, conjugation of ubiquitin from adenyl-ubiquitin to an internal cysteine residue of UBA1, and adenylation of a second molecule of ubiquitin. In the first step, the adenylation module of UBA1 catalyzes the acyl-adenylation of the C-terminal glycine of ubiquitin (Jin et al. 2007, inferred from the rabbit homologue in Haas et al. 1982, Hershko et al. 1983, reviewed in Groettrup et al. 2008).
R-HSA-8852129 (Reactome) In the cytosol, the UBA1-ubiquitin thiol ester conjugate transfers ubiquitin from UBA1 to an internal cysteine residue of the E2 enzyme, forming a thiol ester conjugate between ubiquitin and the cysteine residue of E2 (Jin et al. 2007, inferred from the rabbit homologue in Hershko et al. 1983). The E2 then disengages from UBA1 (Eletr et al. 2005).
R-HSA-8852130 (Reactome) In the nucleus (Grenfell et al. 1994), the UBA1-ubiquitin thiol ester conjugate transfers ubiquitin from UBA1 to an internal cysteine residue of the E2 enzyme, forming a thiol ester conjugate between ubiquitin and the cysteine residue of E2 (Jin et al. 2007, inferred from the rabbit homologue in Hershko et al. 1983, reviewed in Groettrup et al. 2008). The E2 then disengages from UBA1 (Eletr et al. 2005).
R-HSA-8852131 (Reactome) UBA1 is located in both the cytoplasm and nucleus (Grenfell et al. 1994). Activation of ubiquitin by UBA1 proceeds through 3 steps: adenylation of ubiquitin, conjugation of ubiquitin from adenyl-ubiquitin to an internal cysteine residue of UBA1, and adenylation of a second molecule of ubiquitin. In the third step, the UBA1-ubiquitin conjugate adenylates the C-terminal glycine of a second ubiquitin molecule. This results in UBA1 loaded with 2 ubiquitin molecules, one of which is conjugated to an internal cysteine residue of UBA1 and one of which is adenylated and non-covalently bound to UBA1 (Jin et al. 2007, inferred from the rabbit homologue in Haas et al. 1982, Hershko et al. 1983, reviewed in Groettrup et al. 2008)
R-HSA-8852132 (Reactome) Activation of ubiquitin by UBA1 proceeds through 3 steps: adenylation of ubiquitin, conjugation of ubiquitin from adenyl-ubiquitin to an internal cysteine residue of UBA1, and adenylation of a second molecule of ubiquitin. In the third step, the UBA1-ubiquitin conjugate adenylates the C-terminal glycine of a second ubiquitin molecule. This results in UBA1 loaded with 2 ubiquitin molecules, one of which is conjugated to an internal cysteine residue of UBA1 and one of which is adenylated and non-covalently bound to UBA1 (Jin et al. 2007, inferred from the rabbit homologue in Haas et al. 1982, Hershko et al. 1983, reviewed in Groettrup et al. 2008).
R-HSA-8852133 (Reactome) Activation of ubiquitin by UBA1 proceeds through 3 steps: adenylation of ubiquitin, conjugation of ubiquitin from adenyl-ubiquitin to an internal cysteine residue of UBA1, and adenylation of a second molecule of ubiquitin. In the second step, the thiol group of an internal cysteine residue of UBA1 attacks the acyl-adenyl bond of the C-terminal glycine of adenylated ubiquitin, resulting in a thioester bond between the cysteine residue and the C-terminal glycine of ubiquitin (Jin et al. 2007, inferred from the rabbit homologue in Haas et al. 1982, Hershko et al. 1983, reviewed in Groettrup et al. 2008).
R-HSA-8852134 (Reactome) Activation of ubiquitin by UBA1 proceeds through 3 steps: adenylation of ubiquitin, conjugation of ubiquitin from adenyl-ubiquitin to an internal cysteine residue of UBA1, and adenylation of a second molecule of ubiquitin. In the first step the adenylation module of UBA1 catalyzes the acyl-adenylation of the C-terminal glycine of ubiquitin (Jin et al. 2007, inferred from the rabbit homologue in Haas et al. 1982, Hershko et al. 1983, reviewed in Groettrup et al. 2008).
R-HSA-8852136 (Reactome) UBA1 is located in both the nucleus and cytoplasm (Grenfell 1994). Activation of ubiquitin by UBA1 proceeds through 3 steps: adenylation of ubiquitin, conjugation of ubiquitin from adenyl-ubiquitin to an internal cysteine residue of UBA1, and adenylation of a second molecule of ubiquitin. In the second step, the thiol group of an internal cysteine residue of UBA1 attacks the acyl-adenyl bond of the C-terminal glycine of adenylated ubiquitin, resulting in a thioester bond between the cysteine residue and the C-terminal glycine of ubiquitin (Jin et al. 2007, inferred from the rabbit homologue in Haas et al. 1982, Hershko et al. 1983, reviewed in Groettrup et al. 2008).
R-HSA-8853503 (Reactome) The RPS27A precursor protein contains the ribosomal protein L40 and ubiquitin (RPS27A residues 1 to 76) which are released by proteolysis. Any of the proteases UCHL3, USP7, or USP9X can catalyze the proteolysis reaction (Larsen et al. 1998, Grou et al. 2015).
R-HSA-8853514 (Reactome) The UBA52 precursor protein contains the ribosomal protein L40 and ubiquitin (UBA52 residues 1 to 76) which are released by proteolysis. Any of the proteases UCHL3, USP7, or USP9X can catalyze the proteolysis reaction (Larsen et al. 1998, Grou et al. 2015).
R-HSA-8853515 (Reactome) The UBC poly-protein contains 9 Ubiquitin monomers that are released by proteolysis. Either USP5 (Falquet et al. 1995) or OTULIN can perform the proteolyic cleavage reactions (Grou et al. 2015).
R-HSA-8853529 (Reactome) The UBB poly-protein contains 3 Ubiquitin monomers that are released by proteolysis. Either USP5 (Falquet et al. 1995) or OTULIN can perform the proteolyic cleavage reactions (Grou et al. 2015).
R-HSA-8865050 (Reactome) As inferred from the homologous UBA1, activation of ubiquitin by UBA6 (UBE1L1) proceeds through 3 steps: adenylation of ubiquitin, conjugation of ubiquitin from adenyl-ubiquitin to an internal cysteine residue of UBA6, and adenylation of a second molecule of ubiquitin. In the third step, the UBA6-ubiquitin conjugate adenylates the C-terminal glycine of a second ubiquitin molecule. This results in UBA6 loaded with 2 ubiquitin molecules, one of which is conjugated to an internal cysteine residue of UBA6 and one of which is adenylated and non-covalently bound to UBA6 (Jin et al. 2007, Pelzer et al. 2007, reviewed in Groettrup et al. 2008).
R-HSA-8865090 (Reactome) As inferred from the homologous UBA1, activation of ubiquitin by UBA6 (UBE1L1) proceeds through 3 steps: adenylation of ubiquitin, conjugation of ubiquitin from adenyl-ubiquitin to an internal cysteine residue of UBA6, and adenylation of a second molecule of ubiquitin. In the first step, the adenylation module of UBA6 catalyzes the acyl-adenylation of the C-terminal glycine of ubiquitin (Jin et al. 2007, Pelzer et al. 2007, Groettrup et al. 2008).
R-HSA-8865098 (Reactome) As inferred from the homologous UBA1, activation of ubiquitin by UBA6 (UBE1L1) proceeds through 3 steps: adenylation of ubiquitin, conjugation of ubiquitin from adenyl-ubiquitin to an internal cysteine residue of UBA6, and adenylation of a second molecule of ubiquitin. In the second step, the thiol group of an internal cysteine residue of UBA6 attacks the acyl-adenyl bond of the C-terminal glycine of adenylated ubiquitin, resulting in a thioester bond between the cysteine residue and the C-terminal glycine of ubiquitin (Jin et al. 2007, Pelzer et al. 2007, reviewed in Groettrup et al. 2008).
RPL40ArrowR-HSA-8853514 (Reactome)
RPS27A(1-76)ArrowR-HSA-8853503 (Reactome)
RPS27A(77-156)ArrowR-HSA-8853503 (Reactome)
RPS27AR-HSA-8853503 (Reactome)
UBA1:ubiquitin adenylateArrowR-HSA-8852128 (Reactome)
UBA1:ubiquitin adenylateArrowR-HSA-8852129 (Reactome)
UBA1:ubiquitin adenylateArrowR-HSA-8852130 (Reactome)
UBA1:ubiquitin adenylateArrowR-HSA-8852134 (Reactome)
UBA1:ubiquitin adenylateR-HSA-8852133 (Reactome)
UBA1:ubiquitin adenylateR-HSA-8852136 (Reactome)
UBA1:ubiquitin adenylatemim-catalysisR-HSA-8852133 (Reactome)
UBA1R-HSA-8852128 (Reactome)
UBA1R-HSA-8852134 (Reactome)
UBA1mim-catalysisR-HSA-8852134 (Reactome)
UBA52(1-128)R-HSA-8853514 (Reactome)
UBA52(1-76)ArrowR-HSA-8853514 (Reactome)
UBA6:ubiquitin adenylateArrowR-HSA-8852127 (Reactome)
UBA6:ubiquitin adenylateArrowR-HSA-8865090 (Reactome)
UBA6:ubiquitin adenylateR-HSA-8865098 (Reactome)
UBA6:ubiquitin adenylatemim-catalysisR-HSA-8865098 (Reactome)
UBA6R-HSA-8865090 (Reactome)
UBA6mim-catalysisR-HSA-8865090 (Reactome)
UBB(1-76)ArrowR-HSA-8853529 (Reactome)
UBB(153-228)ArrowR-HSA-8853529 (Reactome)
UBB(77-152)ArrowR-HSA-8853529 (Reactome)
UBBR-HSA-8853529 (Reactome)
UBC(1-76)ArrowR-HSA-8853515 (Reactome)
UBC(153-228)ArrowR-HSA-8853515 (Reactome)
UBC(229-304)ArrowR-HSA-8853515 (Reactome)
UBC(305-380)ArrowR-HSA-8853515 (Reactome)
UBC(381-456)ArrowR-HSA-8853515 (Reactome)
UBC(457-532)ArrowR-HSA-8853515 (Reactome)
UBC(533-608)ArrowR-HSA-8853515 (Reactome)
UBC(609-684)ArrowR-HSA-8853515 (Reactome)
UBC(77-152)ArrowR-HSA-8853515 (Reactome)
UBCR-HSA-8853515 (Reactome)
UCHL3,USP7,USP9Xmim-catalysisR-HSA-8853503 (Reactome)
UCHL3,USP7,USP9Xmim-catalysisR-HSA-8853514 (Reactome)
Ub-Cys625-UBA6:ubiquitin adenylateArrowR-HSA-8865050 (Reactome)
Ub-Cys625-UBA6:ubiquitin adenylateR-HSA-8852127 (Reactome)
Ub-Cys625-UBA6ArrowR-HSA-8865098 (Reactome)
Ub-Cys625-UBA6R-HSA-8865050 (Reactome)
Ub-Cys625-UBA6mim-catalysisR-HSA-8865050 (Reactome)
Ub-Cys632-UBA1:ubiquitin adenylateArrowR-HSA-8852131 (Reactome)
Ub-Cys632-UBA1:ubiquitin adenylateArrowR-HSA-8852132 (Reactome)
Ub-Cys632-UBA1:ubiquitin adenylateR-HSA-8852129 (Reactome)
Ub-Cys632-UBA1:ubiquitin adenylateR-HSA-8852130 (Reactome)
Ub-Cys632-UBA1ArrowR-HSA-8852133 (Reactome)
Ub-Cys632-UBA1ArrowR-HSA-8852136 (Reactome)
Ub-Cys632-UBA1R-HSA-8852131 (Reactome)
Ub-Cys632-UBA1R-HSA-8852132 (Reactome)
Ub-Cys632-UBA1mim-catalysisR-HSA-8852132 (Reactome)
Ub:E2 (UBA1 substrate)ArrowR-HSA-8852129 (Reactome)
Ub:E2 (UBA1 substrate)ArrowR-HSA-8852130 (Reactome)
Ub:E2 (UBA6 substrate)ArrowR-HSA-8852127 (Reactome)
UbR-HSA-8852128 (Reactome)
UbR-HSA-8852131 (Reactome)
UbR-HSA-8852132 (Reactome)
UbR-HSA-8852134 (Reactome)
UbR-HSA-8865050 (Reactome)
UbR-HSA-8865090 (Reactome)
adenosine 5'-monophosphateArrowR-HSA-8852136 (Reactome)
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