This protein belongs to the ubiquitin conjugating enzyme family and is one of the E2 enzymes.[11] UBE2Z spans 246 amino acids, 150 of which encode a conserved 16–18 kDa ubiquitin conjugating enzyme E2 domain (UBC domain) that is located at the enzyme’s N-terminal and responsible for the enzyme’s catalytic function. This UBC domain has a relatively inflexible β-sheet structure with flanking helices and contains a highly conserved cysteine residue, Cys80, which functions as an active site for the thiol ester formation with ubiquitin. UBE2Z also contains a C-terminal extension, suggested to participate in substrate binding, which is characteristic of a class II E2 ubiquitin conjugating enzyme.[12]
Function
The UBE2Z gene is ubiquitously expressed in human tissues, and its expression is relatively high in placenta, pancreas, spleen and testis. Notably, its expression in cancer tissues is much higher than in relevant normal tissues, especially in kidney, lymph node, colon and ovary cancer.[12] As an E2 member of the ubiquitin-conjugating enzyme family, UBE2Z mainly participates in the second step of protein ubiquitination, which is a major component of protein degradation machinery.[8] Specifically, UBE2Z receives ubiquitin (Ub) from ubiquitin-activating enzyme (E1), mediates the transfer of Ub from E2 to substrate, directly or indirectly with the help of ligase enzyme (E3), which interacts with the substrate and E2-Ub complex. UBE2Z could only be charged by Ub or FAT10 from UBA6 instead of UBA1, distinguishing it from other E2s.[13][14]
Clinical significance
A study in genetic variants that regulate lipid metabolism and determine the susceptibility to dyslipidemia in Japanese individuals revealed that UBE2Z, together with ZPR1 and Interleukin-6R, may be important loci for hypertriglyceridemia.[15] Moreover, in a GWAS among 2247 Japanese individuals, 29 polymorphisms that were previously identified as susceptible loci for coronary artery disease were investigated to identify a correlation of these loci to chronic kidney disease.[9] This GWAS meta-analysis revealed through a chi-square test that rs46522 on the UBE2Z gene was significantly related to chronic kidney disease.[9]
Clinical marker
A multi-locus genetic risk score study based on a combination of 27 loci, including the UBE2Z gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[10]
^ abBaarends WM, Roest HP, Grootegoed JA (May 1999). "The ubiquitin system in gametogenesis". Molecular and Cellular Endocrinology. 151 (1–2): 5–16. doi:10.1016/s0303-7207(99)00060-x. PMID10411315.
^ abcHoribe H, Fujimaki T, Oguri M, Kato K, Matsuoka R, Abe S, Tokoro F, Arai M, Noda T, Watanabe S, Yamada Y (April 2015). "Association of a polymorphism of the interleukin 6 receptor gene with chronic kidney disease in Japanese individuals". Nephrology. 20 (4): 273–8. doi:10.1111/nep.12381. PMID25524550.
^ abcGu X, Zhao F, Zheng M, Fei X, Chen X, Huang S, Xie Y, Mao Y (September 2007). "Cloning and characterization of a gene encoding the human putative ubiquitin conjugating enzyme E2Z (UBE2Z)". Molecular Biology Reports. 34 (3): 183–8. doi:10.1007/s11033-006-9033-7. PMID17160626.
^Jin J, Li X, Gygi SP, Harper JW (June 2007). "Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging". Nature. 447 (7148): 1135–8. doi:10.1038/nature05902. PMID17597759.
