Ubiquitin-activating enzyme
Encyclopedia
Ubiquitin-activating enzymes, also known as E1 enzymes, catalyze the first step in the ubiquitination reaction, which targets a protein for degradation via a proteasome
. This covalent attachment of ubiquitin
or ubiquitin-like proteins to targeted proteins is a major mechanism for regulating protein function in eukaryotic organisms. Many processes such as cell division, immune responses and embryonic development are also regulated by post-transcriptional modification by ubiquitin and ubiquitin-like proteins.
(E2). The E2 protein complexes with an Ubiquitin protein ligase
(E3). This Ubiquitin protein ligase recognizes which protein needs to be tagged and catalyzes the transfer of ubiquitin to that protein. This pathway repeats itself until the target protein has a full chain of ubiquitin attached to itself.
Throughout this mechanism, the E1 enzyme is bound to two ubiquitin molecules. Although this secondary ubiquitin is similarly adenylated, it does not form the same thioester complex described previously. The function of the secondary ubiquitin remains largely unknown, however it is believed that it may facilitate conformational changes seen in the E1 enzyme during the transthioesterification process.
(XL-SMA). The fatal childhood disorder is associated with loss of anterior horn cells and infantile death. Clinical features include hypotonia, areflexia, and multiple congenital contractures. In a large-scale mutation analysis, screening of six XL-SMA families provided results indicating two novel missense mutations in two families and a novel synonymous C->T substitution in another three families[footnote]. All of these detected mutations were located in exon 15 of the UBE1 gene (the gene encoding ubiquitin-activating enzyme) and were observed to segregate with disease in the families. In brevity, UBE1 missense may lead to a disturbed complex building with gigaxonin, a protein involved in axonal structure and neuronal maintenance. This can lead to impaired degradation of microtubule-associated protein 1B (MAP1B), resulting in the build-up of MAP1B protein, which may enhance neuronal cell death. Thus, mutations in UBE1 are suspected to be the cause of genetic defects in XL-SMA individuals.
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
. This covalent attachment of ubiquitin
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
or ubiquitin-like proteins to targeted proteins is a major mechanism for regulating protein function in eukaryotic organisms. Many processes such as cell division, immune responses and embryonic development are also regulated by post-transcriptional modification by ubiquitin and ubiquitin-like proteins.
Overview of ubiquitination (ubiquitylation)
Ubiquitin-activating enzyme (E1) starts the ubiquitination process (Figure 1). The E1 enzyme along with ATP binds to the ubiquitin protein. The E1 enzyme then passes the ubiquitin protein to a second protein, called Ubiquitin carrier or conjugation proteinUbiquitin-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 covalently attaches ubiquitin, a short protein of 76...
(E2). The E2 protein complexes with an Ubiquitin protein ligase
Ubiquitin ligase
A ubiquitin ligase is a protein that in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome...
(E3). This Ubiquitin protein ligase recognizes which protein needs to be tagged and catalyzes the transfer of ubiquitin to that protein. This pathway repeats itself until the target protein has a full chain of ubiquitin attached to itself.
Structure and mechanism
At the start of the ubiquitination cascade, the E1 enzyme (Figure 2) binds ATP-Mg2+ and ubiquitin and catalyses ubiquitin C-terminal acyl adenylation. In the next step a catalytic cysteine (Figure 3) on the E1 enzyme attacks the ubiquitin-AMP complex through acyl substitution, simultaneously creating a thioester bond and an AMP leaving group. Finally, the E1~ubiquitin complex transfers ubiquitin to an E2 enzyme through a transthioesterification reaction, in which an E2 catalytic cysteine attacks the backside of the E1~ubiquitin complex. However, the transthioesterification process is very complicated, as both E1 and E2 enzymes form an intermediate complex wherein both enzymes undergo a series of conformational changes in order to bind with one another.Throughout this mechanism, the E1 enzyme is bound to two ubiquitin molecules. Although this secondary ubiquitin is similarly adenylated, it does not form the same thioester complex described previously. The function of the secondary ubiquitin remains largely unknown, however it is believed that it may facilitate conformational changes seen in the E1 enzyme during the transthioesterification process.
Isozymes
The following human genes encode ubiquitin-activating enzymes:- UBA1UBE1Ubiquitin-like modifier activating enzyme 1, also known as UBA1, is an enzyme which in humans is encoded by the UBA1 gene.- Function :...
- UBA2
- UBA3UBE1CThis enzyme contains an E2 binding domain, which resembles ubiquitin, and recruits the catalytic core of the E2 enzyme UBE2M in a similar manner to that in which ubiquitin interacts with ubiquitin binding domains.-Interactions:...
- UBA5UBE1DC1Ubiquitin-like modifier-activating enzyme 5 is a protein that in humans is encoded by the UBA5 gene.-Further reading:...
- UBA6UBE1L2Ubiquitin-like modifier-activating enzyme 6 is a protein that in humans is encoded by the UBA6 gene.-Further reading:...
- UBA7UBE1LUbiquitin-like modifier-activating enzyme 7 is a protein that in humans is encoded by the UBA7 gene.-Further reading:...
- ATG7ATG7Autophagy-related protein 7 is a protein that in humans is encoded by the ATG7 gene.-Further reading:...
- NAE1APPBP1NEDD8-activating enzyme E1 regulatory subunit is a protein that in humans is encoded by the NAE1 gene.-Interactions:APPBP1 has been shown to interact with UBE1C, TRIP12 and Amyloid precursor protein.-Further reading:...
- SAE1SAE1SUMO-activating enzyme subunit 1 is a protein that in humans is encoded by the SAE1 gene.-Further reading:...
Disease association
The ubiquitin-proteasome system is critical to appropriate protein degradation within cells. Dysfunctions of this system can disrupt cellular homeostasis and lead to a host of disorders. In normally functioning cells, the covalent linkage of ubiquitin or ubiquitin-like protein to a target protein changes the target protein’s surface. These ubiquitinylated proteins are subject to degradation by proteolytic and non-proteolytic pathways. If this system malfunctions, numerous inherited and acquired diseases may result, such as cancer, diabetes, stroke, Alzheimer’s disease, amyotropic lateral sclerosis, multiple sclerosis, asthma, inflammatory bowl disease, autoimmune thyroiditis, inflammatory arthritis and lupus.Missense in UBE1 and X-linked infantile spinal muscular atrophy (XL-SMA)
Among the various disorders associated with the ubiquitin-proteasome pathway is X-linked infantile spinal muscular atrophySpinal muscular atrophy
Spinal Muscular Atrophy is a neuromuscular disease characterized by degeneration of motor neurons, resulting in progressive muscular atrophy and weakness. The clinical spectrum of SMA ranges from early infant death to normal adult life with only mild weakness...
(XL-SMA). The fatal childhood disorder is associated with loss of anterior horn cells and infantile death. Clinical features include hypotonia, areflexia, and multiple congenital contractures. In a large-scale mutation analysis, screening of six XL-SMA families provided results indicating two novel missense mutations in two families and a novel synonymous C->T substitution in another three families[footnote]. All of these detected mutations were located in exon 15 of the UBE1 gene (the gene encoding ubiquitin-activating enzyme) and were observed to segregate with disease in the families. In brevity, UBE1 missense may lead to a disturbed complex building with gigaxonin, a protein involved in axonal structure and neuronal maintenance. This can lead to impaired degradation of microtubule-associated protein 1B (MAP1B), resulting in the build-up of MAP1B protein, which may enhance neuronal cell death. Thus, mutations in UBE1 are suspected to be the cause of genetic defects in XL-SMA individuals.