UBE2Z

Ubiquitin conjugating enzyme E2 Z (UBE2Z), also known as UBA6-specific E2 enzyme 1 (USE1), is an enzyme that in humans is encoded by the UBE2Z gene on chromosome 17. It is ubiquitously expressed in many tissues and cell types. UBE2Z is an E2 ubiquitin conjugating enzyme and participates in the second step of protein ubiquitination during proteolysis. A genome-wide association study (GWAS) revealed the UBE2Z gene to be associated with chronic kidney disease. The UBE2Z gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

Gene
The UBE2Z gene resides on chromosome 17 at the band 17q21.32 and contains 7 exons. This gene produces 2 isoforms through alternative splicing. The UBE2Z cDNA spans a length of 3,054 base pairs.

Protein
This protein belongs to the ubiquitin conjugating enzyme family and is one of the E2 enzymes. 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.

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. 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. 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.

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. 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. This GWAS meta-analysis revealed through a chi-square test that rs46522 on the UBE2Z gene was significantly related to chronic kidney disease.

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).