The enzymes of the ubiquitylation pathway play a pivotal role in a number of cellular processes including regulated and targeted proteasomal degradation of substrate proteins. Three classes of enzymes are involved in the process of ubiquitylation; activating enzymes (E1s), conjugating enzymes (E2s) and protein ligases (E3s). UBE2E2 is a member of the E2 ubiquitin-conjugating enzyme family and cloning of the human gene was first described by Kimura et al. (1997). The Ubc domain of UBE2E2 shares over 90% identity with human UBE2E1, mouse UbcM2, and Drosophila UbcD2 (Kimura et al., 1997). UBE2E2 has been shown to ubiquitylate the E3 ligase E6AP by binding to its HECT domain (Kumar et al., 1997). A yeast two hybrid screen identified two UBE2E2 binding proteins, UbcH7-Associated Protein (H7-AP1) and Human Homologue of Drosophila ARIadne (HHARI); both of these proteins are characterized by the presence of a RING finger and In Between RING finger (IBR) domains (Moynihan et al., 1999). Studies using deletion mutants of UBE2E2 and two point mutants - ARA54 and C220S - and RNF8 C403S, have demonstrated that ARA54 and RNF8 ring finger proteins interact with the Ubc domain of UBE2E2 (Ito et al., 2001). UBE2E2 binds directly to the BRCA1 RING motif of the human heterodimeric RING E3 ligase complex BRCA1-BARD1 and is active in causing autoubiquitylation in vitro (Christensen et al., 2007). UBE2E2 has also been shown to bind the ubiquitin-protein ligase Parkin via its C-terminal ring-finger domain, resulting in ubiquitylation of the synaptic vesicle associated protein CDCrel-1 (Zhang et al., 2000).
Christensen DE, Brzovic PS, Klevit RE (2007) E2-BRCA1 RING interactions dictate synthesis of mono- or specific polyubiquitin chain linkages. Nat Struct Mol Biol 14, 941-8.
Ito K, Adachi S, Iwakami R, Yasuda H, Muto Y, Seki N, Okano Y (2001) N-Terminally extended human ubiquitin-conjugating enzymes (E2s) mediate the ubiquitination of RING-finger proteins, ARA54 and RNF8. Eur J Biochem 268, 2725-32.
Kimura M, Hattori T, Matsuda Y, Yoshioka T, Sumi N, Umeda Y, Nakashima S, Okano Y (1997) cDNA cloning, characterization, and chromosome mapping of UBE2E2 encoding a human ubiquitin-conjugating E2 enzyme. Cytogenet Cell Genet 78, 107-11.
Kumar S, Kao WH, Howley PM (1997) Physical interaction between specific E2 and Hect E3 enzymes determines functional cooperativity. J Biol Chem 272, 13548-54.
Moynihan TP, Ardley HC, Nuber U, Rose SA, Jones PF, Markham AF, Scheffner M, Robinson PA (1999) The ubiquitin-conjugating enzymes UbcH7 and UbcH8 interact with RING finger/IBR motif-containing domains of HHARI and H7-AP1. J Biol Chem 274, 30963-8.
Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM (2000) Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc Natl Acad Sci USA 97, 13354-9.