UBA2

UBA2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1Y8Q, 1Y8R, 2PX9, 3KYC, 3KYD, 4W5V
Identifiers
Aliases	UBA2, ARX, SAE2, HRIHFB2115, ubiquitin like modifier activating enzyme 2
External IDs	OMIM: 613295; MGI: 1858313; HomoloGene: 4018; GeneCards: UBA2; OMA:UBA2 - orthologs
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19q13.11 Start 34,428,352 bp[1] End 34,471,251 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7|7 B1 Start 33,840,113 bp[2] End 33,869,024 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in ventricular zone ganglionic eminence Achilles tendon popliteal artery tibial arteries right coronary artery gonad left coronary artery thoracic aorta ascending aorta Top expressed in otic placode otic vesicle saccule primitive streak renal corpuscle somite medial ganglionic eminence abdominal wall mandibular prominence superior cervical ganglion More reference expression data BioGPS n/a
Gene ontology Molecular function metal ion binding nucleotide binding enzyme activator activity ubiquitin-like modifier activating enzyme activity transcription factor binding protein binding SUMO activating enzyme activity magnesium ion binding ATP binding SUMO binding small protein activating enzyme binding ubiquitin-like protein conjugating enzyme binding protein heterodimerization activity acid-amino acid ligase activity transferase activity Cellular component nucleus SUMO activating enzyme complex nucleoplasm cytoplasm Biological process protein sumoylation positive regulation of catalytic activity protein modification by small protein conjugation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10054 50995 Ensembl ENSG00000126261 ENSMUSG00000052997 UniProt Q9UBT2 Q9Z1F9 RefSeq (mRNA) NM_005499 NM_016682 RefSeq (protein) NP_005490 NP_057891 Location (UCSC) Chr 19: 34.43 – 34.47 Mb Chr 7: 33.84 – 33.87 Mb PubMed search [3] [4]
Wikidata
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Ubiquitin-like 1-activating enzyme E1B (UBLE1B) also known as SUMO-activating enzyme subunit 2 (SAE2) is an enzyme that in humans is encoded by the UBA2 gene.^[5]

Posttranslational modification of proteins by the addition of the small protein SUMO (see SUMO1), or sumoylation, regulates protein structure and intracellular localization. SAE1 and UBA2 form a heterodimer that functions as a SUMO-activating enzyme for the sumoylation of proteins.^[5][6]

Structure

DNA

The UBA2 cDNA fragment 2683 bp long and encodes a peptide of 640 amino acids.^[6] The predicted protein sequence is more analogous to yeast UBA2 (35% identity) than human UBA3 or E1 (in ubiquitin pathway). The UBA gene is located on chromosome 19.^[7]

Protein

Uba2 subunit is 640 aa residues long with a molecular weight of 72 kDa.^[8] It consists of three domains: an adenylation domain (containing adenylation active site), a catalytic Cys domain (containing the catalytic Cys173 residue participated in thioester bond formation), and a ubiquitin-like domain. SUMO-1 binds on Uba2 between the catalytic Cys domain and UbL domain.^[9]

Mechanism

SUMO activating enzyme (E1, heterodimer of SAE1 and UBA2) catalyzes the reaction of activating SUMO-1 and transferring it to Ubc9 (the only known E2 for SUMOylation). The reaction happens in three steps: adenylation, thioester bond formation, and SUMO transfer to E2. First, the carboxyl group of SUMO C-terminal glycine residue attacks ATP, forming SUMO-AMP and pyrophosphate. Next, the thiol group of a catalytic cysteine in the UBA2 active site attacks SUMO-AMP, forming a high energy thioester bond between UBA2 and the C-terminal glycine of SUMO and releasing AMP. Finally, SUMO is transferred to an E2 cysteine, forming another thioester bond.^[9][10][11]

Function

Ubiquitin tag has a well understood role of directing protein towards degradation by proteasome.^[12] The role SUMO molecules play are more complicated and much less well understood. SUMOylation consequences include altering substrate affinity for other proteins or with DNA, changing substrate localization, and blocking ubiquitin binding (which prevents substrate degradation). For some proteins, SUMOylation doesn’t seem to have a function.^[10][13]

NF-kB

Transcription factor NF-kB in unstimulated cells is inactivated by IkBa inhibitor protein binding. The activation of NF-kB is achieved by ubiquitination and subsequent degradation of IkBa. SUMOylation of IkBa has a strong inhibitory effect on NF-kB-dependent transcription. This may be a mechanism for cell to regulate the number of NF-kB available for transcriptional activation.^[14]

p53

Transcription factor p53 is a tumor suppressor acting by activating genes involved in cell cycle regulation and apoptosis. Its level is regulated by mdm2-dependent ubiquitination. SUMOylation of p53 (at a distinct lysine residue from ubiquitin modification sites) prevents proteasome degradation and acts as an additional regulator to p53 response.^[15]

Expression and regulation

Studies of yeast budding and fission have revealed that SUMOylation may be important in cell cycle regulation.^[16] During a cell cycle, the UBA2 concentration doesn't undergo substantial change while SAE1 level shows dramatic fluctuation, suggesting regulation of SAE1 expression rather than UBA2 might be a way for cell to regulate SUMOylation. However, at time points when SAE1 levels are low, little evidence of UBA2-containing protein complexes are found other than SAE1-UBA2 heterodimer. One possible explanation would be that these complexes exist only for a short period of time, thus not obvious in cell extracts. UBA2 expression is found in most organs including the brain, lung and heart, indicating probable existence of SUMOylation pathway in these organs. An elevated level of UBA2 (as well as all other enzyme components of the pathway) is found in testis, suggesting possible role for UBA2 in meiosis or spermatogenesis. Inside the nucleus, UBA2 is distributed throughout nuclei but not found in nucleoli, suggesting SUMOylation may occur primarily in nuclei. Cytoplasmic existence of SAE 1 and UBA2 is also possible and is responsible for conjugation of cytoplasmic substrates.^[17]

Interactions

SAE2 has been shown to interact with

• SAE1,^{[7][8][18][19]}
• Small ubiquitin-related modifier 1,^[7][20] and
• UBE2I.^[19][21]

References

Further reading

External links

• UBA2 human gene location in the UCSC Genome Browser.
• UBA2 human gene details in the UCSC Genome Browser.