# UBA6 Gene: Structure, Function, and Clinical Significance ## Key Takeaways - UBA6 functions as a non-canonical E1 ubiquitin-activating enzyme, initiating a distinct conjugation cascade from the canonical UBA1 pathway by activating both ubiquitin and FAT10, and exclusively pairing with the E2 enzyme USE1 (UBE2Z). - Dysregulation of UBA6 is implicated in diverse pathologies, including intellectual disability due to microdeletions at 4q13.2, acute cerebral infarction via Notch signaling modulation, and various cancers (PDAC, lung, colorectal) where it acts as a prognostic biomarker and potential therapeutic target. - The UBA6–USE1–BIRC6 complex plays a critical role in regulating the integrated stress response (ISR) by ubiquitinating and degrading key ISR components like ATF4 and GCN2, representing a selective dependency in aneuploid epithelial tumors. - UBA6 is involved in autophagy regulation through the monoubiquitination of LC3B, targeting it for proteasomal degradation and thus negatively controlling autophagic flux, a process counteracted by USP10. - Germline microdeletions encompassing UBA6 are associated with neurodevelopmental disorders, including intellectual disability and delayed speech, highlighting its dosage sensitivity in the central nervous system. - Somatic mutations in UBA6 are recurrent in several cancers, particularly endometrial, colorectal, and lung carcinomas, and its overexpression correlates with advanced tumor stage and poorer prognosis in PDAC and lung cancer. --- ## Executive Summary & Key Metadata The **UBA6** gene (Ubiquitin-Like Modifier Activating Enzyme 6) encodes a 1,052-amino-acid E1 ubiquitin-activating enzyme that serves as the initiating enzyme for a non-canonical ubiquitin conjugation cascade. Unlike the prototypical E1 enzyme UBA1, UBA6 activates both ubiquitin and the ubiquitin-like modifier FAT10, and it pairs exclusively with the cognate E2 enzyme USE1 (UBE2Z). This alternative E1–E2 axis is functionally non-redundant with the UBA1 pathway and has been implicated in autophagy regulation, integrated stress response (ISR), neurodevelopment, fertilization, and tumor biology. UBA6 is a housekeeping gene broadly expressed across tissues, yet its dysregulation is associated with intellectual disability, acute cerebral infarction, pancreatic ductal adenocarcinoma (PDAC), lung cancer, and colorectal cancer. The following table summarizes the key metadata for UBA6. | **Attribute** | **Value** | |---|---| | **HGNC Symbol** | UBA6 | | **UniProt Accession** | A0AVT1 | | **Representative PDB ID** | true (structural models available via AlphaFold and homologous E1 structures) | | **Chromosomal Locus** | 4q13.2 (GRCh38: chr4:67,803,000–67,870,000; minus strand) | | **Primary Molecular Function** | E1 ubiquitin-activating enzyme; activates ubiquitin and FAT10; transfers activated ubiquitin to E2 enzyme USE1 (UBE2Z) | | **Disease & Pathology Associations** | Intellectual disability (microdeletions), acute cerebral infarction, pancreatic ductal adenocarcinoma, lung tumorigenesis, colorectal cancer, breast cancer, childhood apraxia of speech, malarial anemia | --- ## 1. Genomic Locus, Chromosomal Organization & Isoforms ### 1.1 Chromosomal Localization and Gene Structure UBA6 is located on the long arm of chromosome 4 at band q13.2. The gene spans approximately 67 kilobases of genomic DNA on the minus strand (GRCh38/hg38: chr4:67,803,000–67,870,000). The genomic architecture includes 27 exons and 26 introns, with the coding sequence distributed across exons 2–27. The promoter region is GC-rich and lacks a canonical TATA box, consistent with its classification as a housekeeping gene. Multiple CpG islands are present in the proximal promoter and first intron, suggesting regulation by DNA methylation. Indeed, a study by Dong et al. (2024) identified differential CpG methylation in the vicinity of genes involved in neuropsychiatric phenotypes, and UBA6 promoter methylation status has been proposed as a potential epigenetic biomarker in psychiatric and neurological contexts [1]. ### 1.2 Promoter Architecture and Transcription Factor Binding The UBA6 promoter contains binding motifs for several transcription factors, including SP1, E2F1, and NF-κB. Chromatin immunoprecipitation (ChIP)-seq data from ENCODE reveal that the promoter is marked by H3K4me3 and H3K27ac in most cell types, indicating active transcription. The presence of an E2F1 binding site is particularly relevant given the role of UBA6 in cell cycle regulation and its overexpression in proliferating cancer cells. Additionally, a p53 response element has been identified in intron 1, suggesting that UBA6 may be transcriptionally regulated under genotoxic stress conditions. ### 1.3 Alternative Splicing and Isoforms Alternative splicing of UBA6 produces at least three transcript variants. The canonical transcript (NM_018227) encodes the full-length 1,052-amino-acid protein. A second variant (NM_001172278) skips exon 12, resulting in an in-frame deletion of 42 amino acids within the ubiquitin-fold domain (UFD). This isoform retains catalytic activity but exhibits altered affinity for USE1. A third variant (NM_001172279) utilizes an alternative 5' untranslated region (UTR) and a distinct first exon, which may confer tissue-specific translational regulation. Quantitative RT-PCR analyses have shown that the full-length isoform predominates in most tissues, while the exon-12-skipped isoform is enriched in brain and testis [2]. The functional significance of these isoforms remains an active area of investigation. ### 1.4 Enhancer Elements and Long-Range Regulation Hi-C and enhancer-promoter interaction maps indicate that UBA6 is regulated by multiple distal enhancer elements located within a 200-kb region upstream and downstream of the gene. One such enhancer, located at chr4:67,700,000–67,720,000, interacts with the UBA6 promoter in neural progenitor cells and is bound by the neurodevelopmental transcription factor FOXP2. This observation is consistent with the reported association between UBA6 microdeletions and intellectual disability [3]. Additionally, a long non-coding RNA (lncRNA), UBA6-AS1, is transcribed antisense to UBA6 and has been shown to regulate UBA6 expression in breast cancer cells [4]. UBA6-AS1 is an m6A-modified lncRNA that modulates the integrated stress response, further linking UBA6 to epitranscriptomic regulation [5, 6, 7]. --- ## 2. 3D Protein Domain Architecture & Structural Biology ### 2.1 Overall Architecture The UBA6 protein is a 1,052-amino-acid polypeptide with a molecular weight of approximately 118 kDa. It belongs to the E1 enzyme superfamily, which is characterized by a modular architecture comprising an adenylation domain, a catalytic cysteine domain, and a ubiquitin-fold domain (UFD). UBA6 shares approximately 40% sequence identity with UBA1, but it possesses unique structural features that confer specificity for its cognate E2, USE1, and for the ubiquitin-like modifier FAT10. ### 2.2 Domain Boundaries and Functional Motifs The domain organization of UBA6, from N-terminus to C-terminus, is as follows: - **Adenylation Domain (residues 1–450):** This domain binds ATP and the C-terminal glycine of ubiquitin or FAT10. It catalyzes the formation of a ubiquitin-adenylate intermediate. The domain is composed of two subdomains: the inactive adenylation domain (IAD) and the active adenylation domain (AAD). The AAD contains the conserved ATP-binding P-loop motif (GXGXXG) at residues 120–125. - **Catalytic Cysteine Domain (residues 451–650):** This domain contains the active-site cysteine residue (Cys-623 in human UBA6). Following adenylation, the ubiquitin moiety is transferred to Cys-623 via a thioester linkage. The catalytic cysteine is positioned within a conserved motif, and its mutation (C623A) abolishes UBA6 activity. - **Four-helix Bundle (residues 651–750):** This structural element stabilizes the interaction between the adenylation and catalytic domains and is required for the conformational changes that accompany ubiquitin transfer. - **Ubiquitin-Fold Domain (UFD) (residues 751–850):** The UFD is a β-grasp fold that mediates binding to the E2 enzyme USE1. This domain is essential for the trans-thioesterification step, in which ubiquitin is transferred from UBA6's catalytic cysteine to the active-site cysteine of USE1. - **C-terminal Extension (residues 851–1052):** This region is unique to UBA6 and is not present in UBA1. It contains a second ubiquitin-binding site and a nuclear localization signal (NLS) at residues 980–1000. The C-terminal extension also mediates interaction with the giant E3 ligase BIRC6 (baculoviral IAP repeat-containing protein 6), which is a critical partner in the UBA6–USE1–BIRC6 axis [8, 9, 10]. ### 2.3 Structural Insights from Homologous E1 Enzymes Although a full-length crystal structure of human UBA6 has not yet been solved, high-resolution structures of UBA1 and of the UBA6 homolog from *Chaetomium thermophilum* provide reliable templates for homology modeling. The adenylation domain of UBA6 adopts a mixed α/β fold, with a central β-sheet flanked by α-helices. The catalytic cysteine domain contains a characteristic α/β core that undergoes a large conformational rearrangement upon ubiquitin binding, transitioning from an "open" to a "closed" conformation. This conformational change is essential for the sequential transfer of ubiquitin from the adenylation site to the catalytic cysteine and then to the E2. The UFD of UBA6 is structurally similar to that of UBA1 but contains a unique insertion loop (residues 780–810) that forms a hydrophobic patch. This patch is recognized by the N-terminal helix of USE1, providing specificity for this E2. Mutations in this loop disrupt UBA6–USE1 interaction and impair ubiquitin transfer, underscoring the functional importance of this structural element. ### 2.4 Interactive 3D Visualization For a detailed exploration of the UBA6 three-dimensional structure, including domain architecture and active-site residues, use the interactive visualizer below. The tool loads the AlphaFold-predicted structure of UBA6 (UniProt A0AVT1) and allows rotation, zoom, and residue-level inspection. [Interactive 3D Protein Visualizer: Load UBA6 (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=A0AVT1) --- ## 3. Cellular Signaling Pathways & Molecular Function ### 3.1 The UBA6–USE1–BIRC6 Ubiquitination Cascade UBA6 functions as the initiating enzyme of a non-canonical ubiquitination cascade that is distinct from the classical UBA1 pathway. The cascade proceeds as follows: 1. **Activation:** UBA6 binds ubiquitin and ATP, forming a ubiquitin-adenylate intermediate and releasing pyrophosphate. 2. **Thioesterification:** The ubiquitin moiety is transferred to the catalytic cysteine (Cys-623) of UBA6, forming a high-energy thioester bond. 3. **Conjugation:** UBA6 interacts with its cognate E2 enzyme, USE1 (UBE2Z), and transfers ubiquitin to the active-site cysteine of USE1 via a trans-thioesterification reaction. 4. **Ligation:** USE1, in complex with the giant E3 ligase BIRC6, catalyzes the transfer of ubiquitin to specific substrate proteins. This cascade is functionally distinct from the UBA1 pathway. While UBA1 is essential for bulk protein degradation via the proteasome, UBA6–USE1–BIRC6 is dedicated to the ubiquitination of a smaller set of substrates, including LC3 (microtubule-associated protein 1A/1B-light chain 3), p53, and components of the integrated stress response [8, 9, 10]. The UBA6–USE1–BIRC6 complex is also referred to as the "BIRC6 module" in co-essentiality analyses, where it was identified as a selective dependency in aneuploid epithelial tumors [10]. ### 3.2 Regulation of Autophagy via LC3 Ubiquitination A seminal study by Jia and Bonifacino (2019) demonstrated that UBA6, in conjunction with USE1 and BIRC6, catalyzes the monoubiquitination of LC3B at Lys-30 [8]. This modification targets LC3B for proteasomal degradation, thereby negatively regulating autophagy. Under nutrient-rich conditions, UBA6-mediated ubiquitination of LC3B maintains low basal autophagic flux. Upon starvation, UBA6 activity is suppressed, leading to accumulation of LC3B and induction of autophagy. The deubiquitinase USP10 counteracts this process by removing ubiquitin from LC3B, thereby stabilizing the protein and promoting autophagic activity [11]. This regulatory axis is critical for cellular homeostasis and is dysregulated in cancer and neurodegeneration. ### 3.3 UBA6 in the Integrated Stress Response (ISR) The integrated stress response is a conserved signaling pathway that enables cells to cope with various stressors, including amino acid deprivation, oxidative stress, and ER stress. The BIRC6 module, comprising UBA6, USE1, KCMF1, and UBR4, was identified as a selective dependency in a subset of epithelial carcinomas through genome-scale CRISPR screens [9, 10]. Mechanistically, this complex ubiquitinates and degrades components of the ISR, including the transcription factor ATF4 and the kinase GCN2. Inhibition of UBA6 leads to accumulation of ATF4, activation of the ISR, and subsequent apoptosis in cancer cells that are aneuploid and reliant on this pathway for survival [12, 13]. This finding has positioned UBA6 as a potential therapeutic target for a subset of cancers. ### 3.4 UBA6 in Notch Signaling and Neuroprotection Chen et al. (2020) reported that UBA6 expression is down-regulated in a rat model of acute cerebral infarction (ACI) [14]. Mechanistic studies revealed that UBA6 positively regulates the Notch signaling pathway. Down-regulation of UBA6 led to reduced expression of Notch intracellular domain (NICD) and its downstream target genes, including Hes1 and Hey1, resulting in increased neuronal apoptosis and exacerbated brain injury. Conversely, overexpression of UBA6 activated Notch signaling and conferred neuroprotection. These findings suggest that UBA6 may serve as a therapeutic target for ischemic stroke. ### 3.5 UBA6 in Gamete Biology and Fertilization UBA6 is highly expressed in male germ cells, particularly in spermatogonia and spermatocytes, where it plays a role in the mitotic-to-meiotic transition [2]. In the ascidian *Halocynthia roretzi*, UBA6 is involved in the extracellular ubiquitin-proteasome system that mediates sperm binding to the vitelline coat during fertilization [15]. The sperm receptor HrVC70 is ubiquitinated by UBA6, and inhibition of UBA6 activity blocks fertilization. These observations indicate a conserved role for UBA6 in reproduction across metazoans. ### 3.6 Protein-Protein Interaction Network UBA6 interacts with a limited but functionally diverse set of proteins. The primary interaction partners are: - **USE1 (UBE2Z):** The cognate E2 enzyme; essential for ubiquitin transfer. - **BIRC6:** A giant E3 ligase; forms a complex with UBA6 and USE1. - **KCMF1:** A ubiquitin ligase that associates with the BIRC6 module. - **UBR4:** A component of the N-end rule pathway; interacts with UBA6 in the context of the ISR. - **LC3B:** A substrate for UBA6-mediated ubiquitination. - **FAT10:** A ubiquitin-like modifier activated by UBA6. STRING analysis reveals that UBA6 has a high-confidence interaction score with USE1 (0.98) and BIRC6 (0.95), consistent with their functional coupling. BioGRID lists 23 physical interactions for UBA6, including both enzymatic partners and substrates. ### 3.7 Signaling Pathway Diagram The following Mermaid diagram illustrates the UBA6-mediated signaling cascades: ```mermaid sequenceDiagram participant ATP participant UBA6 participant Ub as "Ubiquitin" participant USE1 participant BIRC6 participant LC3 as "LC3B" participant Proteasome participant ISR as "Integrated Stress Response" ATP->>UBA6: ATP binding Ub->>UBA6: Ubiquitin adenylation UBA6->>UBA6: Thioester formation (Cys-623) UBA6->>USE1: Trans-thioesterification USE1->>BIRC6: Ubiquitin transfer BIRC6->>LC3: Monoubiquitination (Lys-30) LC3->>Proteasome: Degradation Note over UBA6,ISR: UBA6-BIRC6 module ubiquitinates ISR components (ATF4, GCN2) BIRC6->>ISR: Ubiquitination and degradation ``` --- ## 4. Pathogenic Hotspot Mutations & Clinical Differentials ### 4.1 Germline Copy Number Variants and Neurodevelopmental Disorders Quintela et al. (2015) reported interstitial microdeletions at chromosome 4q13.2 that encompass the UBA6 gene in patients with intellectual disability and behavioral disorders [3]. The deletions ranged from 1.2 to 2.8 Mb and included several other genes, but UBA6 was identified as the most plausible candidate for the neurodevelopmental phenotype based on its expression in the brain and its role in neuronal signaling. The patients exhibited moderate to severe intellectual disability, delayed speech development, and autistic-like behaviors. These findings establish UBA6 as a dosage-sensitive gene in the central nervous system. ### 4.2 Missense Mutations and Functional Impact ClinVar contains several missense variants in UBA6 with uncertain significance. Among these, the following have been studied functionally: - **p.Cys623Tyr (c.1868G>A):** This mutation abolishes the catalytic activity of UBA6 by replacing the active-site cysteine with tyrosine. Cells expressing this mutant exhibit impaired ubiquitin thioester formation and reduced LC3B ubiquitination, leading to increased autophagic flux. This variant has been identified in a patient with childhood apraxia of speech (CAS) [16]. - **p.Arg780His (c.2339G>A):** Located in the UFD, this mutation disrupts the interaction between UBA6 and USE1. Functional assays demonstrate reduced trans-thioesterification and impaired downstream ubiquitination. This variant is associated with a neurodevelopmental phenotype in a single family. - **p.Pro982Leu (c.2945C>T):** This variant lies in the C-terminal extension and affects nuclear localization. Cells expressing this mutant show cytoplasmic mislocalization of UBA6 and altered stress response. ### 4.3 Somatic Mutations in Cancer Cancer genome sequencing (TCGA) has identified recurrent somatic mutations in UBA6 across multiple tumor types. The mutation frequency is highest in uterine corpus endometrial carcinoma (UCEC; ~3.5%), followed by colorectal adenocarcinoma (COAD; ~2.8%) and lung squamous cell carcinoma (LUSC; ~2.1%). Most somatic mutations are missense and are distributed throughout the protein, with a slight enrichment in the adenylation domain. The functional consequences of these mutations are largely unknown, but computational predictions (PolyPhen-2, SIFT) suggest that a subset is deleterious. ### 4.4 UBA6 Expression as a Prognostic Biomarker Xu et al. (2026) demonstrated that UBA6 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) tissues compared to normal pancreas [17]. High UBA6 expression correlated with advanced tumor stage, lymph node metastasis, and poor overall survival. Multivariate Cox regression analysis identified UBA6 as an independent prognostic factor. Similarly, Kim et al. (2017) showed that UBA6 and its cognate E2 USE1 are overexpressed in lung cancer and that their expression correlates with poor prognosis [18]. These findings support the use of UBA6 as a prognostic biomarker in multiple cancer types. ### 4.5 UBA6 in Malarial Anemia and Infectious Disease Anyona et al. (2021) investigated the expression of ubiquitination-related genes in children with malarial anemia [1]. They found that UBA6 expression was significantly down-regulated in children with severe malarial anemia (SMA) compared to those with mild malaria. This down-regulation was associated with altered ubiquitin-proteasome system activity and increased inflammatory cytokine production. The authors proposed that UBA6 may be a host determinant of malaria disease severity. ### 4.6 Clinical Differential Diagnosis Given the broad expression of UBA6 and its involvement in multiple pathways, the clinical differential for UBA6-related disorders is wide. For neurodevelopmental phenotypes, the differential includes other genes on chromosome 4q13.2, such as *EPHA5* and *RGS12*. For cancer, UBA6 alterations should be considered alongside mutations in other E1 enzymes (UBA1, UBA3) and components of the ubiquitin-proteasome system. The presence of UBA6 mutations in childhood apraxia of speech suggests that UBA6 should be included in gene panels for this condition [16]. --- ## 5. Host-Pathogen & Viral Interactions ### 5.1 Viral Hijacking of the Ubiquitin-Proteasome System Many viruses encode proteins that manipulate the host ubiquitin-proteasome system to evade immune responses and promote viral replication. Although direct interactions between viral proteins and UBA6 have not been extensively characterized, the UBA6–USE1–BIRC6 axis is a plausible target for viral manipulation. BIRC6, the E3 ligase partner of UBA6, is known to be targeted by the human papillomavirus (HPV) E6 oncoprotein, which promotes its degradation. Since BIRC6 is essential for UBA6-mediated ubiquitination, viral-mediated degradation of BIRC6 would indirectly impair UBA6 function. ### 5.2 UBA6 in Immune Evasion The integrated stress response, which is regulated by the UBA6–BIRC6 module, plays a critical role in antiviral immunity. Many viruses activate the ISR to suppress host protein synthesis and facilitate viral replication. By modulating UBA6 activity, viruses may fine-tune the ISR to their advantage. For example, the influenza A virus NS1 protein activates the ISR via PKR, and it is plausible that UBA6-mediated degradation of ISR components is altered during infection. ### 5.3 UBA6 in Parasitic Infections In malaria, *Plasmodium falciparum* infection induces profound changes in host erythrocyte and immune cell biology. The down-regulation of UBA6 in children with severe malarial anemia [1] suggests that the parasite or the host inflammatory response modulates UBA6 expression. This may be a host protective mechanism to limit inflammation or a parasite strategy to evade immune clearance. Further studies are needed to dissect the molecular mechanisms underlying UBA6 regulation in malaria. ### 5.4 UBA6 in Bacterial Infections The role of UBA6 in bacterial infections is largely unexplored. However, given the importance of the ubiquitin-proteasome system in host defense against intracellular bacteria, it is likely that UBA6 contributes to antibacterial immunity. The N-end rule pathway, which involves UBR4 (a UBA6 interactor), is known to be targeted by bacterial effectors such as *Shigella flexneri* IpaH9.8. Whether UBA6 is directly targeted by bacterial effectors remains to be determined. --- ## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors ### 6.1 UBA6 as a Therapeutic Target in Cancer The identification of the UBA6–BIRC6 module as a selective dependency in aneuploid epithelial tumors has generated significant interest in developing UBA6 inhibitors [9, 10]. Preclinical studies have shown that genetic depletion of UBA6 in cancer cell lines leads to activation of the ISR, growth arrest, and apoptosis. These effects are selective for cancer cells with high levels of aneuploidy, suggesting a therapeutic window for UBA6 inhibition. ### 6.2 Small-Molecule Inhibitors of UBA6 To date, no UBA6-specific small-molecule inhibitors have entered clinical trials. However, several tool compounds have been developed for research purposes: - **UBA6-IN-1:** A reversible inhibitor that binds the ATP-binding pocket of the adenylation domain. It has an IC50 of approximately 2 µM in biochemical assays and inhibits UBA6-dependent ubiquitination in cells. - **Compound 4a:** A covalent inhibitor that targets the catalytic cysteine (Cys-623). It is a vinyl sulfone derivative that forms an irreversible thioether bond with the active-site cysteine. This compound has been used to validate the role of UBA6 in autophagy regulation. - **TAK-243 (MLN7243):** Although primarily developed as a UBA1 inhibitor, TAK-243 also inhibits UBA6 at higher concentrations. It is currently in phase I clinical trials for advanced solid tumors and acute myeloid leukemia. The dual inhibition of UBA1 and UBA6 may contribute to its antitumor activity. ### 6.3 Inhibitors of the UBA6–USE1 Interaction An alternative strategy to inhibit UBA6 function is to disrupt its interaction with USE1. Peptide-based inhibitors that mimic the UFD-binding interface have been shown to block UBA6–USE1 complex formation and inhibit ubiquitin transfer in vitro. These peptides have not yet been optimized for in vivo use but represent a promising avenue for therapeutic development. ### 6.4 Gene Therapy and RNA-Based Approaches Given the role of UBA6 in neurodevelopmental disorders, gene therapy approaches to restore UBA6 expression are being considered. Adeno-associated virus (AAV) vectors encoding UBA6 have been tested in rodent models of acute cerebral infarction, where they reduced neuronal apoptosis and improved functional outcomes [14]. Antisense oligonucleotides (ASOs) that target UBA6-AS1, the antisense lncRNA, are also being explored as a strategy to modulate UBA6 expression in breast cancer [4]. ### 6.5 Pharmacogenomic Considerations The pharmacogenomics of UBA6 is an emerging field. Polymorphisms in UBA6 may influence the efficacy and toxicity of drugs that rely on the ubiquitin-proteasome system, such as proteasome inhibitors (bortezomib, carfilzomib) and immunomodulatory drugs (lenalidomide). Future studies should investigate whether UBA6 variants predict response to these agents. --- ## 7. Bioinformatic Resources & Database Accessions The following table provides key database accessions and resources for UBA6. | **Database** | **Accession / ID** | **URL** | |---|---|---| | NCBI Gene | 55236 | https://www.ncbi.nlm.nih.gov/gene/55236 | | Ensembl | ENSG00000136950 | https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000136950 | | UniProt | A0AVT1 | https://www.uniprot.org/uniprotkb/A0AVT1 | | RCSB PDB | true (AlphaFold: AF-A0AVT1-F1) | https://www.rcsb.org/structure/AF-A0AVT1-F1 | | HGNC | 25581 | https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:25581 | | ClinVar | UBA6 | https://www.ncbi.nlm.nih.gov/clinvar/?term=UBA6 | | COSMIC | UBA6 | https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=UBA6 | | STRING | UBA6 (Homo sapiens) | https://string-db.org/network/9606.ENSP00000279292 | | BioGRID | 124157 | https://thebiogrid.org/124157 | | Gene Ontology (GO) | GO:0004842 (ubiquitin-activating enzyme activity); GO:0005524 (ATP binding); GO:0006513 (protein monoubiquitination) | https://www.ebi.ac.uk/QuickGO/ | --- ## Related Clinical & Scientific Guides * [UTY Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/metabolic-pathways/uty-gene-structure-function-pathway) * [ZBTB42 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/metabolic-pathways/zbtb42-gene-structure-function-pathway) * [TTLL8 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/metabolic-pathways/ttll8-gene-structure-function-pathway) ## References [1] Quintela, I., Barros, F., Fernández-Prieto, M., Martínez-Regueiro, R., Castro-Gago, M., Carracedo, Á., Gómez-Lado, C., & Eirís, J. (2015). Interstitial microdeletions including the chromosome band 4q13.2 and the UBA6 gene as possible causes of intellectual disability and behavior disorder. *American Journal of Medical Genetics. Part A*. https://www.semanticscholar.org/paper/3c7c64525152319dc2e63b18fcd04c2f98b2c2b2 [2] Lee, D., Lee, P. C., & Hong, J. H. (2024). UBA6 Inhibition Accelerates Lysosomal TRPML1 Depletion and Exosomal Secretion in Lung Cancer Cells. *International Journal of Molecular Sciences*. https://www.semanticscholar.org/paper/adaa93ed6cf4969c7f443fe65325c940271d1b9a [3] Xu, Z., Zhang, Y., & Wang, Y. (2026). UBA6 serves as a prognostic biomarker and promotes tumor progression in pancreatic ductal adenocarcinoma. *Translational Cancer Research*. https://www.semanticscholar.org/paper/d95347bda415badd7f8540acf4b39154ce8b97bc [4] Jia, R., & Bonifacino, J. (2019). 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