Ubiquitin conjugating enzyme E2 Z (UBE2Z), also known as UBA6-specific E2 enzyme 1 (USE1), is an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

that in humans is encoded by the ''UBE2Z'' gene on

chromosome 17 Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 84 million base pairs (the building material of DNA) and represents between 2.5 and 3% of the total DN ...

. 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 Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 19 ...

during

proteolysis Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Protein degradation is a major regulatory mechanism of gene expression and contributes substantially to shaping mammalian proteomes. Uncatalysed, the hydrolysis o ...

. A

genome-wide association study In genomics, a genome-wide association study (GWA study, or GWAS), is an observational study of a genome-wide set of Single-nucleotide polymorphism, genetic variants in different individuals to see if any variant is associated with a trait. GWA s ...

(GWAS) revealed the UBE2Z gene to be associated with

chronic kidney disease Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...

. The ''UBE2Z'' gene also contains one of 27

SNPs In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...

associated with increased risk of

coronary artery disease Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of cardiovascular disease, heart disease involving Ischemia, the reduction of blood flow to the cardiac muscle due to a build-up ...

Structure

Gene

The ''UBE2Z'' gene resides on chromosome 17 at the band 17q21.32 and contains 7

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

s. This gene produces 2

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

through

alternative splicing Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...

. The UBE2Z

cDNA In genetics, complementary DNA (cDNA) is DNA that was reverse transcribed (via reverse transcriptase) from an RNA (e.g., messenger RNA or microRNA). cDNA exists in both single-stranded and double-stranded forms and in both natural and engin ...

spans a length of 3,054

base pair A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...

Protein

This protein belongs to the ubiquitin conjugating enzyme family and is one of the E2 enzymes. UBE2Z spans 246

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

s, 150 of which encode a conserved 16–18

kDa The dalton or unified atomic mass unit (symbols: Da or u, respectively) is a unit of mass defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at rest. It is a non-SI unit accepted f ...

ubiquitin conjugating enzyme E2 domain (UBC domain) that is located at the enzyme’s

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

and responsible for the enzyme’s

catalytic Catalysis () is the increase in reaction rate, rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst ...

function. This UBC domain has a relatively inflexible

β-sheet The beta sheet (β-sheet, also β-pleated sheet) is a common structural motif, motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone chain, backbon ...

structure with flanking helices and contains a highly conserved

cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

residue, Cys80, which functions as an

active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate, the ''binding s ...

for the thiol ester formation with ubiquitin. UBE2Z also contains a

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...

extension, suggested to participate in

substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (aquatic environment), the earthy material that exi ...

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 The placenta (: placentas or placentae) is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas, and waste exchange between ...

pancreas The pancreas (plural pancreases, or pancreata) is an Organ (anatomy), organ of the Digestion, digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a ...

spleen The spleen (, from Ancient Greek '' σπλήν'', splḗn) is an organ (biology), organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The spleen plays important roles in reg ...

and

testis A testicle or testis ( testes) is the gonad in all male bilaterians, including humans, and is Homology (biology), homologous to the ovary in females. Its primary functions are the production of sperm and the secretion of Androgen, androgens, p ...

. 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 Ubiquitin-conjugating enzymes, also known as E2 enzymes and more rarely as ''ubiquitin-carrier enzymes'', perform the second step in the ubiquitination reaction that targets a protein for degradation via the proteasome. The ubiquitination process ...

family, UBE2Z mainly participates in the second step of protein

, which is a major component of protein degradation machinery. Specifically, UBE2Z receives

ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 19 ...

(Ub) from

ubiquitin-activating enzyme Ubiquitin-activating enzymes, also known as E1 enzymes, catalyze the first step in the ubiquitination reaction, which (among other things) can target a protein for degradation via a proteasome. This covalent bond of ubiquitin or ubiquitin-like pro ...

(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).

References

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