Synthesis of active ubiquitin: roles of E1 and E2 enzymes

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Homo sapiens
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Ubiquitin monomers are processed from larger precursors and then activated by formation of a thiol ester bond between ubiquitin and a cysteine residue of an E1 activating enzyme (UBA1 or UBA6, Jin et al. 2007). The ubiquitin is then transferred to the active site cysteine residue of an E2 conjugating enzyme (reviewed in van Wijk and Timmers 2010, Kleiger and Mayor 2014, Stewart et al. 2016). Precursor proteins containing multiple ubiquitin monomers (polyubiquitins) are produced from the UBB and UBC genes. Precursors containing a single ubiquitin fused to a ribosomal protein are produced from the UBA52 and RPS27A genes. The proteases OTULIN and USP5 are very active in polyubiquitin processing, whereas the proteases UCHL3, USP7, and USP9X cleave the ubiquitin-ribosomal protein precursors yielding ubiquitin monomers (Grou et al. 2015). Other enzymes may also process ubiquitin precursors. A resultant ubiquitin monomer is activated by adenylation of its 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 (Jin et al. 2007, inferred from rabbit homologues in Haas et al. 1982, Hershko et al. 1983). 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).

Literature References
PubMed ID Title Journal Year
26235645 The de novo synthesis of ubiquitin: identification of deubiquitinases acting on ubiquitin precursors

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

Sci Rep 2015
27002219 E2 enzymes: more than just middle men

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

Cell Res. 2016
17597759 Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging

Li, X, Gygi, SP, Jin, J, Harper, JW

Nature 2007
6277905 Ubiquitin-activating enzyme. Mechanism and role in protein-ubiquitin conjugation

Rose, IA, Hershko, A, Haas, AL, Warms, JV

J. Biol. Chem. 1982
19940261 The family of ubiquitin-conjugating enzymes (E2s): deciding between life and death of proteins

Timmers, HT, van Wijk, SJ

FASEB J 2010
6305978 Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown

Ciechanover, A, Elias, S, Heller, H, Hershko, A

J. Biol. Chem. 1983
24457024 Perilous journey: a tour of the ubiquitin-proteasome system

Mayor, T, Kleiger, G

Trends Cell Biol. 2014
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