Protein ubiquitination

Stable Identifier
R-HSA-8852135
Type
Pathway
Species
Homo sapiens
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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).

Literature References
PubMed ID Title Journal Year
27002219 E2 enzymes: more than just middle men

Stewart, MD, Ritterhoff, T, Klevit, RE, Brzovic, PS

Cell Res. 2016
23624913 SCFs in the new millennium

Lee, EK, Diehl, JA

Oncogene 2014
19436320 Physiological functions of the HECT family of ubiquitin ligases

Rotin, D, Kumar, S

Nat. Rev. Mol. Cell Biol. 2009
23061719 The significance of ubiquitin proteasome pathway in cancer development

Yerlikaya, A, Yƶntem, M

Recent Pat Anticancer Drug Discov 2013
22389392 HECT and RING finger families of E3 ubiquitin ligases at a glance

Metzger, MB, Hristova, VA, Weissman, AM

J. Cell. Sci. 2012
19940261 The family of ubiquitin-conjugating enzymes (E2s): deciding between life and death of proteins

van Wijk, SJ, Timmers, HT

FASEB J 2010
23657496 Mechanisms and function of substrate recruitment by F-box proteins

Skaar, JR, Pagan, JK, Pagano, M

Nat. Rev. Mol. Cell Biol. 2013
23800009 Macromolecular juggling by ubiquitylation enzymes

Lorenz, S, Cantor, AJ, Rape, M, Kuriyan, J

BMC Biol. 2013
19775879 Control of cell growth by the SCF and APC/C ubiquitin ligases

Skaar, JR, Pagano, M

Curr. Opin. Cell Biol. 2009
24457024 Perilous journey: a tour of the ubiquitin-proteasome system

Kleiger, G, Mayor, T

Trends Cell Biol. 2014
23732108 Non-canonical ubiquitylation: mechanisms and consequences

McDowell, GS, Philpott, A

Int. J. Biochem. Cell Biol. 2013
21883762 Ubiquitination of substrates by esterification

Wang, X, Herr, RA, Hansen, TH

Traffic 2012
26085183 Protein monoubiquitylation: targets and diverse functions

Nakagawa, T, Nakayama, K

Genes Cells 2015
19754430 The emerging complexity of protein ubiquitination

Komander, D

Biochem. Soc. Trans. 2009
25175772 The ubiquitin system in immune regulation

Park, Y, Jin, HS, Aki, D, Lee, J, Liu, YC

Adv. Immunol. 2014
27312108 Molecular insights into RBR E3 ligase ubiquitin transfer mechanisms

Dove, KK, Stieglitz, B, Duncan, ED, Rittinger, K, Klevit, RE

EMBO Rep. 2016
24652853 Regulation of stem cell function by protein ubiquitylation

Strikoudis, A, Guillamot, M, Aifantis, I

EMBO Rep. 2014
26235645 The de novo synthesis of ubiquitin: identification of deubiquitinases acting on ubiquitin precursors

Grou, CP, Pinto, MP, Mendes, AV, Domingues, P, Azevedo, JE

Sci Rep 2015
19489725 RING domain E3 ubiquitin ligases

Deshaies, RJ, Joazeiro, CA

Annu Rev Biochem 2009
23747565 RING-type E3 ligases: master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination

Metzger, MB, Pruneda, JN, Klevit, RE, Weissman, AM

Biochim. Biophys. Acta 2014
22708562 Enzymes of ubiquitination and deubiquitination

Neutzner, M, Neutzner, A

Essays Biochem. 2012
24699078 New insights into ubiquitin E3 ligase mechanism

Berndsen, CE, Wolberger, C

Nat. Struct. Mol. Biol. 2014
26187467 Regulating the Regulators: Recent Revelations in the Control of E3 Ubiquitin Ligases

Vittal, V, Stewart, MD, Brzovic, PS, Klevit, RE

J. Biol. Chem. 2015
23912815 The emerging family of CULLIN3-RING ubiquitin ligases (CRL3s): cellular functions and disease implications

Genschik, P, Sumara, I, Lechner, E

EMBO J. 2013
17588513 DCAFs, the missing link of the CUL4-DDB1 ubiquitin ligase

Lee, J, Zhou, P

Mol Cell 2007
25815272 Modulation of Immune Cell Functions by the E3 Ligase Cbl-b

Lutz-Nicoladoni, C, Wolf, D, Sopper, S

Front Oncol 2015
25833379 Ubiquitylation, neddylation and the DNA damage response

Brown, JS, Jackson, SP

Open Biol 2015
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