ARIH1 encodes HHARI, an intracellular Ariadne/RBR E3 ubiquitin ligase that catalyzes ubiquitin transfer through a RING1-IBR-RING2 mechanism and is activated by neddylated cullin-RING ligase complexes, especially SCF assemblies, to prime ubiquitination of constrained CRL substrates.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: cytoplasm localization is supported for intracellular ARIH1; the most relevant functional locations are cytoplasm/cytosol and nucleus. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In tumor/pathology and cell-based studies, ARIH1 was detected in both **cytoplasm and nucleus** by staining, consistent with a role in diverse protein quality control and regulatory circuits. In the core mechanistic work, ARIH1 localizes functionally through **complex formation** with neddylated CRL assemblies (e.g., SCF). |
| GO:0031624 ubiquitin conjugating enzyme binding | IBA GO_REF:0000033 | ACCEPT | Summary: ARIH1 binding to ubiquitin-conjugating enzymes is part of its core RBR catalytic cycle, with UBE2L3/UbcH7 the best-supported donor E2. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. file:human/ARIH1/ARIH1-uniprot.txt bind E2s via the first RING-type zinc finger |
| GO:0006511 ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: ubiquitin-dependent protein catabolic process is supported by the catalytic role of ARIH1 in ubiquitination and downstream ubiquitin-dependent substrate turnover, especially as a CRL-associated priming E3. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md A major current paradigm is that **neddylated CRLs recruit and activate ARIH-family RBR ligases**. Neddylation-induced conformational changes in cullins enable catalysis and can relieve ARIH autoinhibition; ARIH1 then performs the catalytic ubiquitin transfer while the CRL scaffold handles substrate recruitment and E2 positioning. file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. |
| GO:0061630 ubiquitin protein ligase activity | IBA GO_REF:0000033 | ACCEPT | Summary: ubiquitin protein ligase activity is a core ARIH1 function: ARIH1/HHARI is an RBR E3 that transfers ubiquitin from an E2 enzyme through its catalytic cysteine to substrates. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md RBR E3 ligases are defined by a **RING1–IBR–RING2** module and use a **two-step** RING/HECT-hybrid catalytic mechanism. In step 1, a ubiquitin-charged E2 binds **RING1** and transfers ubiquitin to the E3’s **RING2 catalytic cysteine** (a **transthiolation** reaction). In step 2, ubiquitin is transferred from the E3~Ub thioester to a substrate lysine (aminolysis). This general mechanism explicitly includes **HHARI/ARIH1** as a canonical member. file:human/ARIH1/ARIH1-uniprot.txt bind E2s via the first RING-type zinc finger |
| GO:0000151 ubiquitin ligase complex | IBA GO_REF:0000033 | ACCEPT | Summary: ARIH1 forms functional ubiquitin ligase assemblies with neddylated CRLs; this broad complex annotation captures that E3-ligase-complex context. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md A major current paradigm is that **neddylated CRLs recruit and activate ARIH-family RBR ligases**. Neddylation-induced conformational changes in cullins enable catalysis and can relieve ARIH autoinhibition; ARIH1 then performs the catalytic ubiquitin transfer while the CRL scaffold handles substrate recruitment and E2 positioning. file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: nucleus localization is supported for intracellular ARIH1; the most relevant functional locations are cytoplasm/cytosol and nucleus. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In tumor/pathology and cell-based studies, ARIH1 was detected in both **cytoplasm and nucleus** by staining, consistent with a role in diverse protein quality control and regulatory circuits. In the core mechanistic work, ARIH1 localizes functionally through **complex formation** with neddylated CRL assemblies (e.g., SCF). |
| GO:0004842 ubiquitin-protein transferase activity | IEA GO_REF:0000002 | ACCEPT | Summary: ubiquitin-protein transferase activity is a core ARIH1 function: ARIH1/HHARI is an RBR E3 that transfers ubiquitin from an E2 enzyme through its catalytic cysteine to substrates. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md RBR E3 ligases are defined by a **RING1–IBR–RING2** module and use a **two-step** RING/HECT-hybrid catalytic mechanism. In step 1, a ubiquitin-charged E2 binds **RING1** and transfers ubiquitin to the E3’s **RING2 catalytic cysteine** (a **transthiolation** reaction). In step 2, ubiquitin is transferred from the E3~Ub thioester to a substrate lysine (aminolysis). This general mechanism explicitly includes **HHARI/ARIH1** as a canonical member. file:human/ARIH1/ARIH1-uniprot.txt bind E2s via the first RING-type zinc finger |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: nucleus localization is supported for intracellular ARIH1; the most relevant functional locations are cytoplasm/cytosol and nucleus. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In tumor/pathology and cell-based studies, ARIH1 was detected in both **cytoplasm and nucleus** by staining, consistent with a role in diverse protein quality control and regulatory circuits. In the core mechanistic work, ARIH1 localizes functionally through **complex formation** with neddylated CRL assemblies (e.g., SCF). |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: cytoplasm localization is supported for intracellular ARIH1; the most relevant functional locations are cytoplasm/cytosol and nucleus. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In tumor/pathology and cell-based studies, ARIH1 was detected in both **cytoplasm and nucleus** by staining, consistent with a role in diverse protein quality control and regulatory circuits. In the core mechanistic work, ARIH1 localizes functionally through **complex formation** with neddylated CRL assemblies (e.g., SCF). |
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: ARIH1 contains RING/IBR/RING zinc-finger domains required for its RBR E3 mechanism, so zinc ion binding is supported. Supporting Evidence: file:human/ARIH1/ARIH1-uniprot.txt bind E2s via the first RING-type zinc finger |
| GO:0015030 Cajal body | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Cajal body is retained as a reported localization or colocalization but is not part of the core ARIH1 ubiquitin-ligase mechanism. Supporting Evidence: file:human/ARIH1/ARIH1-uniprot.txt Nucleus, Cajal body file:human/ARIH1/ARIH1-uniprot.txt Present in Lewy body |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000120 | ACCEPT | Summary: protein ubiquitination is supported by the catalytic role of ARIH1 in ubiquitination and downstream ubiquitin-dependent substrate turnover, especially as a CRL-associated priming E3. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md A major current paradigm is that **neddylated CRLs recruit and activate ARIH-family RBR ligases**. Neddylation-induced conformational changes in cullins enable catalysis and can relieve ARIH autoinhibition; ARIH1 then performs the catalytic ubiquitin transfer while the CRL scaffold handles substrate recruitment and E2 positioning. file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. |
| GO:0046872 metal ion binding | IEA GO_REF:0000002 | MODIFY | Summary: The metal-binding evidence is specifically zinc binding by RING/IBR/RING domains; the broad metal ion binding term should be replaced by zinc ion binding. Reason: Specific zinc-binding domains are known; the generic metal ion binding term is less informative. Proposed replacements: zinc ion binding Supporting Evidence: file:human/ARIH1/ARIH1-uniprot.txt bind E2s via the first RING-type zinc finger |
| GO:0061630 ubiquitin protein ligase activity | IEA GO_REF:0000003 | ACCEPT | Summary: ubiquitin protein ligase activity is a core ARIH1 function: ARIH1/HHARI is an RBR E3 that transfers ubiquitin from an E2 enzyme through its catalytic cysteine to substrates. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md RBR E3 ligases are defined by a **RING1–IBR–RING2** module and use a **two-step** RING/HECT-hybrid catalytic mechanism. In step 1, a ubiquitin-charged E2 binds **RING1** and transfers ubiquitin to the E3’s **RING2 catalytic cysteine** (a **transthiolation** reaction). In step 2, ubiquitin is transferred from the E3~Ub thioester to a substrate lysine (aminolysis). This general mechanism explicitly includes **HHARI/ARIH1** as a canonical member. file:human/ARIH1/ARIH1-uniprot.txt bind E2s via the first RING-type zinc finger |
| GO:0005515 protein binding | IPI PMID:21145461 Dynamics of cullin-RING ubiquitin ligase network revealed by... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is over-broad for ARIH1. The informative interaction annotations are E2 binding and CRL/SCF association. Reason: Replace generic binding with mechanistically specific E2 or ubiquitin-ligase-complex binding where possible. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. |
| GO:0005515 protein binding | IPI PMID:21532592 UBCH7 reactivity profile reveals parkin and HHARI to be RING... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is over-broad for ARIH1. The informative interaction annotations are E2 binding and CRL/SCF association. Reason: Replace generic binding with mechanistically specific E2 or ubiquitin-ligase-complex binding where possible. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. |
| GO:0005515 protein binding | IPI PMID:23707686 Structure of HHARI, a RING-IBR-RING ubiquitin ligase: autoin... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is over-broad for ARIH1. The informative interaction annotations are E2 binding and CRL/SCF association. Reason: Replace generic binding with mechanistically specific E2 or ubiquitin-ligase-complex binding where possible. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. |
| GO:0005515 protein binding | IPI PMID:24076655 TRIAD1 and HHARI bind to and are activated by distinct neddy... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is over-broad for ARIH1. The informative interaction annotations are E2 binding and CRL/SCF association. Reason: Replace generic binding with mechanistically specific E2 or ubiquitin-ligase-complex binding where possible. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is over-broad for ARIH1. The informative interaction annotations are E2 binding and CRL/SCF association. Reason: Replace generic binding with mechanistically specific E2 or ubiquitin-ligase-complex binding where possible. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is over-broad for ARIH1. The informative interaction annotations are E2 binding and CRL/SCF association. Reason: Replace generic binding with mechanistically specific E2 or ubiquitin-ligase-complex binding where possible. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: nucleoplasm localization is supported for intracellular ARIH1; the most relevant functional locations are cytoplasm/cytosol and nucleus. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In tumor/pathology and cell-based studies, ARIH1 was detected in both **cytoplasm and nucleus** by staining, consistent with a role in diverse protein quality control and regulatory circuits. In the core mechanistic work, ARIH1 localizes functionally through **complex formation** with neddylated CRL assemblies (e.g., SCF). |
| GO:0039585 PKR/eIFalpha signaling | TAS Reactome:R-HSA-9833482 | KEEP AS NON CORE | Summary: PKR/eIFalpha signaling is a pathway-level consequence in Reactome rather than the core molecular role of ARIH1; keep it as non-core while prioritizing ubiquitin/ubiquitin-like ligase activity. Supporting Evidence: file:human/ARIH1/ARIH1-uniprot.txt Acts as the ligase involved in ISGylation of EIF4E2 (PubMed:17289916). |
| GO:0061662 ISG15 ligase activity | TAS Reactome:R-HSA-1169394 | KEEP AS NON CORE | Summary: ISG15 ligase activity is retained as a confirmed secondary ubiquitin-like/ISGylation function: UniProt explicitly states that ARIH1 acts as the ligase involved in ISGylation of EIF4E2, while the dominant core function remains ubiquitin transfer with neddylated CRLs. Reason: Secondary confirmed ubiquitin-like function, not the dominant ARIH1 core activity synthesized from current CRL/RBR literature. Supporting Evidence: file:human/ARIH1/ARIH1-uniprot.txt Acts as the ligase involved in ISGylation of EIF4E2 (PubMed:17289916). file:human/ARIH1/ARIH1-deep-research-falcon.md older literature reported interaction with **UBE2L3 and UBE2L6** |
| GO:0061662 ISG15 ligase activity | TAS Reactome:R-HSA-1169395 | KEEP AS NON CORE | Summary: ISG15 ligase activity is retained as a confirmed secondary ubiquitin-like/ISGylation function: UniProt explicitly states that ARIH1 acts as the ligase involved in ISGylation of EIF4E2, while the dominant core function remains ubiquitin transfer with neddylated CRLs. Reason: Secondary confirmed ubiquitin-like function, not the dominant ARIH1 core activity synthesized from current CRL/RBR literature. Supporting Evidence: file:human/ARIH1/ARIH1-uniprot.txt Acts as the ligase involved in ISGylation of EIF4E2 (PubMed:17289916). file:human/ARIH1/ARIH1-deep-research-falcon.md older literature reported interaction with **UBE2L3 and UBE2L6** |
| GO:0061662 ISG15 ligase activity | TAS Reactome:R-HSA-1169398 | KEEP AS NON CORE | Summary: ISG15 ligase activity is retained as a confirmed secondary ubiquitin-like/ISGylation function: UniProt explicitly states that ARIH1 acts as the ligase involved in ISGylation of EIF4E2, while the dominant core function remains ubiquitin transfer with neddylated CRLs. Reason: Secondary confirmed ubiquitin-like function, not the dominant ARIH1 core activity synthesized from current CRL/RBR literature. Supporting Evidence: file:human/ARIH1/ARIH1-uniprot.txt Acts as the ligase involved in ISGylation of EIF4E2 (PubMed:17289916). file:human/ARIH1/ARIH1-deep-research-falcon.md older literature reported interaction with **UBE2L3 and UBE2L6** |
| GO:0061662 ISG15 ligase activity | TAS Reactome:R-HSA-1169402 | KEEP AS NON CORE | Summary: ISG15 ligase activity is retained as a confirmed secondary ubiquitin-like/ISGylation function: UniProt explicitly states that ARIH1 acts as the ligase involved in ISGylation of EIF4E2, while the dominant core function remains ubiquitin transfer with neddylated CRLs. Reason: Secondary confirmed ubiquitin-like function, not the dominant ARIH1 core activity synthesized from current CRL/RBR literature. Supporting Evidence: file:human/ARIH1/ARIH1-uniprot.txt Acts as the ligase involved in ISGylation of EIF4E2 (PubMed:17289916). file:human/ARIH1/ARIH1-deep-research-falcon.md older literature reported interaction with **UBE2L3 and UBE2L6** |
| GO:0061662 ISG15 ligase activity | TAS Reactome:R-HSA-1169405 | KEEP AS NON CORE | Summary: ISG15 ligase activity is retained as a confirmed secondary ubiquitin-like/ISGylation function: UniProt explicitly states that ARIH1 acts as the ligase involved in ISGylation of EIF4E2, while the dominant core function remains ubiquitin transfer with neddylated CRLs. Reason: Secondary confirmed ubiquitin-like function, not the dominant ARIH1 core activity synthesized from current CRL/RBR literature. Supporting Evidence: file:human/ARIH1/ARIH1-uniprot.txt Acts as the ligase involved in ISGylation of EIF4E2 (PubMed:17289916). file:human/ARIH1/ARIH1-deep-research-falcon.md older literature reported interaction with **UBE2L3 and UBE2L6** |
| GO:0061662 ISG15 ligase activity | TAS Reactome:R-HSA-1169406 | KEEP AS NON CORE | Summary: ISG15 ligase activity is retained as a confirmed secondary ubiquitin-like/ISGylation function: UniProt explicitly states that ARIH1 acts as the ligase involved in ISGylation of EIF4E2, while the dominant core function remains ubiquitin transfer with neddylated CRLs. Reason: Secondary confirmed ubiquitin-like function, not the dominant ARIH1 core activity synthesized from current CRL/RBR literature. Supporting Evidence: file:human/ARIH1/ARIH1-uniprot.txt Acts as the ligase involved in ISGylation of EIF4E2 (PubMed:17289916). file:human/ARIH1/ARIH1-deep-research-falcon.md older literature reported interaction with **UBE2L3 and UBE2L6** |
| GO:0061662 ISG15 ligase activity | TAS Reactome:R-HSA-9833973 | KEEP AS NON CORE | Summary: ISG15 ligase activity is retained as a confirmed secondary ubiquitin-like/ISGylation function: UniProt explicitly states that ARIH1 acts as the ligase involved in ISGylation of EIF4E2, while the dominant core function remains ubiquitin transfer with neddylated CRLs. Reason: Secondary confirmed ubiquitin-like function, not the dominant ARIH1 core activity synthesized from current CRL/RBR literature. Supporting Evidence: file:human/ARIH1/ARIH1-uniprot.txt Acts as the ligase involved in ISGylation of EIF4E2 (PubMed:17289916). file:human/ARIH1/ARIH1-deep-research-falcon.md older literature reported interaction with **UBE2L3 and UBE2L6** |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:23707686 Structure of HHARI, a RING-IBR-RING ubiquitin ligase: autoin... | ACCEPT | Summary: ubiquitin-protein transferase activity is a core ARIH1 function: ARIH1/HHARI is an RBR E3 that transfers ubiquitin from an E2 enzyme through its catalytic cysteine to substrates. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md RBR E3 ligases are defined by a **RING1–IBR–RING2** module and use a **two-step** RING/HECT-hybrid catalytic mechanism. In step 1, a ubiquitin-charged E2 binds **RING1** and transfers ubiquitin to the E3’s **RING2 catalytic cysteine** (a **transthiolation** reaction). In step 2, ubiquitin is transferred from the E3~Ub thioester to a substrate lysine (aminolysis). This general mechanism explicitly includes **HHARI/ARIH1** as a canonical member. file:human/ARIH1/ARIH1-uniprot.txt bind E2s via the first RING-type zinc finger |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:24076655 TRIAD1 and HHARI bind to and are activated by distinct neddy... | ACCEPT | Summary: ubiquitin-protein transferase activity is a core ARIH1 function: ARIH1/HHARI is an RBR E3 that transfers ubiquitin from an E2 enzyme through its catalytic cysteine to substrates. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md RBR E3 ligases are defined by a **RING1–IBR–RING2** module and use a **two-step** RING/HECT-hybrid catalytic mechanism. In step 1, a ubiquitin-charged E2 binds **RING1** and transfers ubiquitin to the E3’s **RING2 catalytic cysteine** (a **transthiolation** reaction). In step 2, ubiquitin is transferred from the E3~Ub thioester to a substrate lysine (aminolysis). This general mechanism explicitly includes **HHARI/ARIH1** as a canonical member. file:human/ARIH1/ARIH1-uniprot.txt bind E2s via the first RING-type zinc finger |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:27565346 Two Distinct Types of E3 Ligases Work in Unison to Regulate ... | ACCEPT | Summary: ubiquitin-protein transferase activity is a core ARIH1 function: ARIH1/HHARI is an RBR E3 that transfers ubiquitin from an E2 enzyme through its catalytic cysteine to substrates. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md RBR E3 ligases are defined by a **RING1–IBR–RING2** module and use a **two-step** RING/HECT-hybrid catalytic mechanism. In step 1, a ubiquitin-charged E2 binds **RING1** and transfers ubiquitin to the E3’s **RING2 catalytic cysteine** (a **transthiolation** reaction). In step 2, ubiquitin is transferred from the E3~Ub thioester to a substrate lysine (aminolysis). This general mechanism explicitly includes **HHARI/ARIH1** as a canonical member. file:human/ARIH1/ARIH1-uniprot.txt bind E2s via the first RING-type zinc finger |
| GO:0005737 cytoplasm | IDA PMID:23059369 Human Homolog of Drosophila Ariadne (HHARI) is a marker of c... | ACCEPT | Summary: cytoplasm localization is supported for intracellular ARIH1; the most relevant functional locations are cytoplasm/cytosol and nucleus. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In tumor/pathology and cell-based studies, ARIH1 was detected in both **cytoplasm and nucleus** by staining, consistent with a role in diverse protein quality control and regulatory circuits. In the core mechanistic work, ARIH1 localizes functionally through **complex formation** with neddylated CRL assemblies (e.g., SCF). |
| GO:0008270 zinc ion binding | IDA PMID:23707686 Structure of HHARI, a RING-IBR-RING ubiquitin ligase: autoin... | ACCEPT | Summary: ARIH1 contains RING/IBR/RING zinc-finger domains required for its RBR E3 mechanism, so zinc ion binding is supported. Supporting Evidence: file:human/ARIH1/ARIH1-uniprot.txt bind E2s via the first RING-type zinc finger |
| GO:0016567 protein ubiquitination | IDA PMID:23707686 Structure of HHARI, a RING-IBR-RING ubiquitin ligase: autoin... | ACCEPT | Summary: protein ubiquitination is supported by the catalytic role of ARIH1 in ubiquitination and downstream ubiquitin-dependent substrate turnover, especially as a CRL-associated priming E3. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md A major current paradigm is that **neddylated CRLs recruit and activate ARIH-family RBR ligases**. Neddylation-induced conformational changes in cullins enable catalysis and can relieve ARIH autoinhibition; ARIH1 then performs the catalytic ubiquitin transfer while the CRL scaffold handles substrate recruitment and E2 positioning. file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. |
| GO:0016567 protein ubiquitination | IDA PMID:24076655 TRIAD1 and HHARI bind to and are activated by distinct neddy... | ACCEPT | Summary: protein ubiquitination is supported by the catalytic role of ARIH1 in ubiquitination and downstream ubiquitin-dependent substrate turnover, especially as a CRL-associated priming E3. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md A major current paradigm is that **neddylated CRLs recruit and activate ARIH-family RBR ligases**. Neddylation-induced conformational changes in cullins enable catalysis and can relieve ARIH autoinhibition; ARIH1 then performs the catalytic ubiquitin transfer while the CRL scaffold handles substrate recruitment and E2 positioning. file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. |
| GO:0016567 protein ubiquitination | IDA PMID:27565346 Two Distinct Types of E3 Ligases Work in Unison to Regulate ... | ACCEPT | Summary: protein ubiquitination is supported by the catalytic role of ARIH1 in ubiquitination and downstream ubiquitin-dependent substrate turnover, especially as a CRL-associated priming E3. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md A major current paradigm is that **neddylated CRLs recruit and activate ARIH-family RBR ligases**. Neddylation-induced conformational changes in cullins enable catalysis and can relieve ARIH autoinhibition; ARIH1 then performs the catalytic ubiquitin transfer while the CRL scaffold handles substrate recruitment and E2 positioning. file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. |
| GO:0016604 nuclear body | IDA PMID:23059369 Human Homolog of Drosophila Ariadne (HHARI) is a marker of c... | KEEP AS NON CORE | Summary: nuclear body is retained as a reported localization or colocalization but is not part of the core ARIH1 ubiquitin-ligase mechanism. Supporting Evidence: file:human/ARIH1/ARIH1-uniprot.txt Nucleus, Cajal body file:human/ARIH1/ARIH1-uniprot.txt Present in Lewy body |
| GO:0019005 SCF ubiquitin ligase complex | IDA PMID:24076655 TRIAD1 and HHARI bind to and are activated by distinct neddy... | ACCEPT | Summary: SCF ubiquitin ligase complex association is part of the best-supported ARIH1 mechanism: ARIH1 cooperates with neddylated SCF complexes as a catalytic E3-E3 super-assembly for CRL substrate ubiquitination. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md A major current paradigm is that **neddylated CRLs recruit and activate ARIH-family RBR ligases**. Neddylation-induced conformational changes in cullins enable catalysis and can relieve ARIH autoinhibition; ARIH1 then performs the catalytic ubiquitin transfer while the CRL scaffold handles substrate recruitment and E2 positioning. file:human/ARIH1/ARIH1-uniprot.txt Associates with cullin-RING ubiquitin ligase (CRL) complexes containing CUL1, CUL2 and CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL1 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL2 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL4A (PubMed:24076655). |
| GO:0019005 SCF ubiquitin ligase complex | IDA PMID:27565346 Two Distinct Types of E3 Ligases Work in Unison to Regulate ... | ACCEPT | Summary: SCF ubiquitin ligase complex association is part of the best-supported ARIH1 mechanism: ARIH1 cooperates with neddylated SCF complexes as a catalytic E3-E3 super-assembly for CRL substrate ubiquitination. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md A major current paradigm is that **neddylated CRLs recruit and activate ARIH-family RBR ligases**. Neddylation-induced conformational changes in cullins enable catalysis and can relieve ARIH autoinhibition; ARIH1 then performs the catalytic ubiquitin transfer while the CRL scaffold handles substrate recruitment and E2 positioning. file:human/ARIH1/ARIH1-uniprot.txt Associates with cullin-RING ubiquitin ligase (CRL) complexes containing CUL1, CUL2 and CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL1 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL2 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL4A (PubMed:24076655). |
| GO:0031462 Cul2-RING ubiquitin ligase complex | IDA NOT PMID:27565346 Two Distinct Types of E3 Ligases Work in Unison to Regulate ... | KEEP AS NON CORE | Summary: This NOT-qualified Cul2-RING complex annotation is retained as a non-core, experiment-specific negative result from PMID:27565346, but it conflicts with positive CUL2 interaction evidence from PMID:24076655 and with UniProt text citing both PMID:24076655 and PMID:27565346 for neddylated CUL2 interaction. The most defensible interpretation is context-dependent assay behavior rather than a global absence of CUL2 association. Reason: Preserve the GOA NOT qualifier while explicitly flagging the conflict with broader positive CUL2 evidence. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md A major current paradigm is that **neddylated CRLs recruit and activate ARIH-family RBR ligases**. Neddylation-induced conformational changes in cullins enable catalysis and can relieve ARIH autoinhibition; ARIH1 then performs the catalytic ubiquitin transfer while the CRL scaffold handles substrate recruitment and E2 positioning. file:human/ARIH1/ARIH1-uniprot.txt Associates with cullin-RING ubiquitin ligase (CRL) complexes containing CUL1, CUL2 and CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL1 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL2 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL4A (PubMed:24076655). |
| GO:0031462 Cul2-RING ubiquitin ligase complex | IDA PMID:24076655 TRIAD1 and HHARI bind to and are activated by distinct neddy... | KEEP AS NON CORE | Summary: Positive Cul2-RING complex association is retained as a non-core CRL context for ARIH1. This should be read alongside the separate NOT-qualified PMID:27565346 annotation, which likely reflects a context-specific negative assay rather than a global absence of CUL2 interaction. Reason: ARIH1-CRL cooperation is well supported, but individual cullin-complex annotations are context annotations rather than the core catalytic function. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md A major current paradigm is that **neddylated CRLs recruit and activate ARIH-family RBR ligases**. Neddylation-induced conformational changes in cullins enable catalysis and can relieve ARIH autoinhibition; ARIH1 then performs the catalytic ubiquitin transfer while the CRL scaffold handles substrate recruitment and E2 positioning. file:human/ARIH1/ARIH1-uniprot.txt Associates with cullin-RING ubiquitin ligase (CRL) complexes containing CUL1, CUL2 and CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL1 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL2 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL4A (PubMed:24076655). |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:24076655 TRIAD1 and HHARI bind to and are activated by distinct neddy... | KEEP AS NON CORE | Summary: Cul3-RING ubiquitin ligase complex association is supported as a CRL partnership for ARIH1; it is retained as a non-core complex context rather than the core catalytic activity itself. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md A major current paradigm is that **neddylated CRLs recruit and activate ARIH-family RBR ligases**. Neddylation-induced conformational changes in cullins enable catalysis and can relieve ARIH autoinhibition; ARIH1 then performs the catalytic ubiquitin transfer while the CRL scaffold handles substrate recruitment and E2 positioning. file:human/ARIH1/ARIH1-uniprot.txt Associates with cullin-RING ubiquitin ligase (CRL) complexes containing CUL1, CUL2 and CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL1 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL2 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL4A (PubMed:24076655). |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:27565346 Two Distinct Types of E3 Ligases Work in Unison to Regulate ... | KEEP AS NON CORE | Summary: Cul3-RING ubiquitin ligase complex association is supported as a CRL partnership for ARIH1; it is retained as a non-core complex context rather than the core catalytic activity itself. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md A major current paradigm is that **neddylated CRLs recruit and activate ARIH-family RBR ligases**. Neddylation-induced conformational changes in cullins enable catalysis and can relieve ARIH autoinhibition; ARIH1 then performs the catalytic ubiquitin transfer while the CRL scaffold handles substrate recruitment and E2 positioning. file:human/ARIH1/ARIH1-uniprot.txt Associates with cullin-RING ubiquitin ligase (CRL) complexes containing CUL1, CUL2 and CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL1 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL2 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL4A (PubMed:24076655). |
| GO:0031464 Cul4A-RING E3 ubiquitin ligase complex | IDA PMID:24076655 TRIAD1 and HHARI bind to and are activated by distinct neddy... | KEEP AS NON CORE | Summary: Cul4A-RING E3 ubiquitin ligase complex association is supported as a CRL partnership for ARIH1; it is retained as a non-core complex context rather than the core catalytic activity itself. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md A major current paradigm is that **neddylated CRLs recruit and activate ARIH-family RBR ligases**. Neddylation-induced conformational changes in cullins enable catalysis and can relieve ARIH autoinhibition; ARIH1 then performs the catalytic ubiquitin transfer while the CRL scaffold handles substrate recruitment and E2 positioning. file:human/ARIH1/ARIH1-uniprot.txt Associates with cullin-RING ubiquitin ligase (CRL) complexes containing CUL1, CUL2 and CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL1 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL2 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL4A (PubMed:24076655). |
| GO:0031624 ubiquitin conjugating enzyme binding | IPI PMID:23707686 Structure of HHARI, a RING-IBR-RING ubiquitin ligase: autoin... | ACCEPT | Summary: ARIH1 binding to ubiquitin-conjugating enzymes is part of its core RBR catalytic cycle, with UBE2L3/UbcH7 the best-supported donor E2. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. file:human/ARIH1/ARIH1-uniprot.txt bind E2s via the first RING-type zinc finger |
| GO:0031624 ubiquitin conjugating enzyme binding | IPI PMID:24076655 TRIAD1 and HHARI bind to and are activated by distinct neddy... | ACCEPT | Summary: ARIH1 binding to ubiquitin-conjugating enzymes is part of its core RBR catalytic cycle, with UBE2L3/UbcH7 the best-supported donor E2. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. file:human/ARIH1/ARIH1-uniprot.txt bind E2s via the first RING-type zinc finger |
| GO:0031624 ubiquitin conjugating enzyme binding | IPI PMID:27565346 Two Distinct Types of E3 Ligases Work in Unison to Regulate ... | ACCEPT | Summary: ARIH1 binding to ubiquitin-conjugating enzymes is part of its core RBR catalytic cycle, with UBE2L3/UbcH7 the best-supported donor E2. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. file:human/ARIH1/ARIH1-uniprot.txt bind E2s via the first RING-type zinc finger |
| GO:0097413 Lewy body | IDA PMID:21590270 The parkin-like human homolog of Drosophila ariadne-1 (HHARI... | KEEP AS NON CORE | Summary: Lewy body is retained as a reported localization or colocalization but is not part of the core ARIH1 ubiquitin-ligase mechanism. Supporting Evidence: file:human/ARIH1/ARIH1-uniprot.txt Nucleus, Cajal body file:human/ARIH1/ARIH1-uniprot.txt Present in Lewy body |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1169394 | ACCEPT | Summary: cytosol localization is supported for intracellular ARIH1; the most relevant functional locations are cytoplasm/cytosol and nucleus. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In tumor/pathology and cell-based studies, ARIH1 was detected in both **cytoplasm and nucleus** by staining, consistent with a role in diverse protein quality control and regulatory circuits. In the core mechanistic work, ARIH1 localizes functionally through **complex formation** with neddylated CRL assemblies (e.g., SCF). |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1169395 | ACCEPT | Summary: cytosol localization is supported for intracellular ARIH1; the most relevant functional locations are cytoplasm/cytosol and nucleus. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In tumor/pathology and cell-based studies, ARIH1 was detected in both **cytoplasm and nucleus** by staining, consistent with a role in diverse protein quality control and regulatory circuits. In the core mechanistic work, ARIH1 localizes functionally through **complex formation** with neddylated CRL assemblies (e.g., SCF). |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1169398 | ACCEPT | Summary: cytosol localization is supported for intracellular ARIH1; the most relevant functional locations are cytoplasm/cytosol and nucleus. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In tumor/pathology and cell-based studies, ARIH1 was detected in both **cytoplasm and nucleus** by staining, consistent with a role in diverse protein quality control and regulatory circuits. In the core mechanistic work, ARIH1 localizes functionally through **complex formation** with neddylated CRL assemblies (e.g., SCF). |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1169402 | ACCEPT | Summary: cytosol localization is supported for intracellular ARIH1; the most relevant functional locations are cytoplasm/cytosol and nucleus. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In tumor/pathology and cell-based studies, ARIH1 was detected in both **cytoplasm and nucleus** by staining, consistent with a role in diverse protein quality control and regulatory circuits. In the core mechanistic work, ARIH1 localizes functionally through **complex formation** with neddylated CRL assemblies (e.g., SCF). |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1169403 | ACCEPT | Summary: cytosol localization is supported for intracellular ARIH1; the most relevant functional locations are cytoplasm/cytosol and nucleus. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In tumor/pathology and cell-based studies, ARIH1 was detected in both **cytoplasm and nucleus** by staining, consistent with a role in diverse protein quality control and regulatory circuits. In the core mechanistic work, ARIH1 localizes functionally through **complex formation** with neddylated CRL assemblies (e.g., SCF). |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1169405 | ACCEPT | Summary: cytosol localization is supported for intracellular ARIH1; the most relevant functional locations are cytoplasm/cytosol and nucleus. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In tumor/pathology and cell-based studies, ARIH1 was detected in both **cytoplasm and nucleus** by staining, consistent with a role in diverse protein quality control and regulatory circuits. In the core mechanistic work, ARIH1 localizes functionally through **complex formation** with neddylated CRL assemblies (e.g., SCF). |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1169406 | ACCEPT | Summary: cytosol localization is supported for intracellular ARIH1; the most relevant functional locations are cytoplasm/cytosol and nucleus. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In tumor/pathology and cell-based studies, ARIH1 was detected in both **cytoplasm and nucleus** by staining, consistent with a role in diverse protein quality control and regulatory circuits. In the core mechanistic work, ARIH1 localizes functionally through **complex formation** with neddylated CRL assemblies (e.g., SCF). |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1678843 | ACCEPT | Summary: cytosol localization is supported for intracellular ARIH1; the most relevant functional locations are cytoplasm/cytosol and nucleus. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In tumor/pathology and cell-based studies, ARIH1 was detected in both **cytoplasm and nucleus** by staining, consistent with a role in diverse protein quality control and regulatory circuits. In the core mechanistic work, ARIH1 localizes functionally through **complex formation** with neddylated CRL assemblies (e.g., SCF). |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9833973 | ACCEPT | Summary: cytosol localization is supported for intracellular ARIH1; the most relevant functional locations are cytoplasm/cytosol and nucleus. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In tumor/pathology and cell-based studies, ARIH1 was detected in both **cytoplasm and nucleus** by staining, consistent with a role in diverse protein quality control and regulatory circuits. In the core mechanistic work, ARIH1 localizes functionally through **complex formation** with neddylated CRL assemblies (e.g., SCF). |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9837231 | ACCEPT | Summary: cytosol localization is supported for intracellular ARIH1; the most relevant functional locations are cytoplasm/cytosol and nucleus. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In tumor/pathology and cell-based studies, ARIH1 was detected in both **cytoplasm and nucleus** by staining, consistent with a role in diverse protein quality control and regulatory circuits. In the core mechanistic work, ARIH1 localizes functionally through **complex formation** with neddylated CRL assemblies (e.g., SCF). |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9927247 | ACCEPT | Summary: cytosol localization is supported for intracellular ARIH1; the most relevant functional locations are cytoplasm/cytosol and nucleus. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In tumor/pathology and cell-based studies, ARIH1 was detected in both **cytoplasm and nucleus** by staining, consistent with a role in diverse protein quality control and regulatory circuits. In the core mechanistic work, ARIH1 localizes functionally through **complex formation** with neddylated CRL assemblies (e.g., SCF). |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:14623119 Human homologue of ariadne promotes the ubiquitylation of tr... | ACCEPT | Summary: ubiquitin-protein transferase activity is a core ARIH1 function: ARIH1/HHARI is an RBR E3 that transfers ubiquitin from an E2 enzyme through its catalytic cysteine to substrates. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md RBR E3 ligases are defined by a **RING1–IBR–RING2** module and use a **two-step** RING/HECT-hybrid catalytic mechanism. In step 1, a ubiquitin-charged E2 binds **RING1** and transfers ubiquitin to the E3’s **RING2 catalytic cysteine** (a **transthiolation** reaction). In step 2, ubiquitin is transferred from the E3~Ub thioester to a substrate lysine (aminolysis). This general mechanism explicitly includes **HHARI/ARIH1** as a canonical member. file:human/ARIH1/ARIH1-uniprot.txt bind E2s via the first RING-type zinc finger |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:15236971 Structure of the C-terminal RING finger from a RING-IBR-RING... | ACCEPT | Summary: ubiquitin-protein transferase activity is a core ARIH1 function: ARIH1/HHARI is an RBR E3 that transfers ubiquitin from an E2 enzyme through its catalytic cysteine to substrates. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md RBR E3 ligases are defined by a **RING1–IBR–RING2** module and use a **two-step** RING/HECT-hybrid catalytic mechanism. In step 1, a ubiquitin-charged E2 binds **RING1** and transfers ubiquitin to the E3’s **RING2 catalytic cysteine** (a **transthiolation** reaction). In step 2, ubiquitin is transferred from the E3~Ub thioester to a substrate lysine (aminolysis). This general mechanism explicitly includes **HHARI/ARIH1** as a canonical member. file:human/ARIH1/ARIH1-uniprot.txt bind E2s via the first RING-type zinc finger |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:21532592 UBCH7 reactivity profile reveals parkin and HHARI to be RING... | ACCEPT | Summary: ubiquitin-protein transferase activity is a core ARIH1 function: ARIH1/HHARI is an RBR E3 that transfers ubiquitin from an E2 enzyme through its catalytic cysteine to substrates. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md RBR E3 ligases are defined by a **RING1–IBR–RING2** module and use a **two-step** RING/HECT-hybrid catalytic mechanism. In step 1, a ubiquitin-charged E2 binds **RING1** and transfers ubiquitin to the E3’s **RING2 catalytic cysteine** (a **transthiolation** reaction). In step 2, ubiquitin is transferred from the E3~Ub thioester to a substrate lysine (aminolysis). This general mechanism explicitly includes **HHARI/ARIH1** as a canonical member. file:human/ARIH1/ARIH1-uniprot.txt bind E2s via the first RING-type zinc finger |
| GO:0005515 protein binding | IPI PMID:14623119 Human homologue of ariadne promotes the ubiquitylation of tr... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is over-broad for ARIH1. The informative interaction annotations are E2 binding and CRL/SCF association. Reason: Replace generic binding with mechanistically specific E2 or ubiquitin-ligase-complex binding where possible. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. |
| GO:0005737 cytoplasm | IDA PMID:11278816 Features of the parkin/ariadne-like ubiquitin ligase, HHARI,... | ACCEPT | Summary: cytoplasm localization is supported for intracellular ARIH1; the most relevant functional locations are cytoplasm/cytosol and nucleus. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In tumor/pathology and cell-based studies, ARIH1 was detected in both **cytoplasm and nucleus** by staining, consistent with a role in diverse protein quality control and regulatory circuits. In the core mechanistic work, ARIH1 localizes functionally through **complex formation** with neddylated CRL assemblies (e.g., SCF). |
| GO:0008270 zinc ion binding | IDA PMID:15236971 Structure of the C-terminal RING finger from a RING-IBR-RING... | ACCEPT | Summary: ARIH1 contains RING/IBR/RING zinc-finger domains required for its RBR E3 mechanism, so zinc ion binding is supported. Supporting Evidence: file:human/ARIH1/ARIH1-uniprot.txt bind E2s via the first RING-type zinc finger |
| GO:0016567 protein ubiquitination | IDA PMID:14623119 Human homologue of ariadne promotes the ubiquitylation of tr... | ACCEPT | Summary: protein ubiquitination is supported by the catalytic role of ARIH1 in ubiquitination and downstream ubiquitin-dependent substrate turnover, especially as a CRL-associated priming E3. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md A major current paradigm is that **neddylated CRLs recruit and activate ARIH-family RBR ligases**. Neddylation-induced conformational changes in cullins enable catalysis and can relieve ARIH autoinhibition; ARIH1 then performs the catalytic ubiquitin transfer while the CRL scaffold handles substrate recruitment and E2 positioning. file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. |
| GO:0016567 protein ubiquitination | IDA PMID:15236971 Structure of the C-terminal RING finger from a RING-IBR-RING... | ACCEPT | Summary: protein ubiquitination is supported by the catalytic role of ARIH1 in ubiquitination and downstream ubiquitin-dependent substrate turnover, especially as a CRL-associated priming E3. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md A major current paradigm is that **neddylated CRLs recruit and activate ARIH-family RBR ligases**. Neddylation-induced conformational changes in cullins enable catalysis and can relieve ARIH autoinhibition; ARIH1 then performs the catalytic ubiquitin transfer while the CRL scaffold handles substrate recruitment and E2 positioning. file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. |
| GO:0016567 protein ubiquitination | IDA PMID:21532592 UBCH7 reactivity profile reveals parkin and HHARI to be RING... | ACCEPT | Summary: protein ubiquitination is supported by the catalytic role of ARIH1 in ubiquitination and downstream ubiquitin-dependent substrate turnover, especially as a CRL-associated priming E3. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md A major current paradigm is that **neddylated CRLs recruit and activate ARIH-family RBR ligases**. Neddylation-induced conformational changes in cullins enable catalysis and can relieve ARIH autoinhibition; ARIH1 then performs the catalytic ubiquitin transfer while the CRL scaffold handles substrate recruitment and E2 positioning. file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:11278816 Features of the parkin/ariadne-like ubiquitin ligase, HHARI,... | KEEP AS NON CORE | Summary: Specific binding to ubiquitin ligase complexes is supported through ARIH1 cooperation with neddylated CRLs, but it is a complex-association context rather than the primary catalytic function. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md A major current paradigm is that **neddylated CRLs recruit and activate ARIH-family RBR ligases**. Neddylation-induced conformational changes in cullins enable catalysis and can relieve ARIH autoinhibition; ARIH1 then performs the catalytic ubiquitin transfer while the CRL scaffold handles substrate recruitment and E2 positioning. file:human/ARIH1/ARIH1-uniprot.txt Associates with cullin-RING ubiquitin ligase (CRL) complexes containing CUL1, CUL2 and CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL1 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL2 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL4A (PubMed:24076655). |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:21532592 UBCH7 reactivity profile reveals parkin and HHARI to be RING... | KEEP AS NON CORE | Summary: Specific binding to ubiquitin ligase complexes is supported through ARIH1 cooperation with neddylated CRLs, but it is a complex-association context rather than the primary catalytic function. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md A major current paradigm is that **neddylated CRLs recruit and activate ARIH-family RBR ligases**. Neddylation-induced conformational changes in cullins enable catalysis and can relieve ARIH autoinhibition; ARIH1 then performs the catalytic ubiquitin transfer while the CRL scaffold handles substrate recruitment and E2 positioning. file:human/ARIH1/ARIH1-uniprot.txt Associates with cullin-RING ubiquitin ligase (CRL) complexes containing CUL1, CUL2 and CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL1 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL2 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL4A (PubMed:24076655). |
| GO:0005515 protein binding | IPI PMID:10521492 The ubiquitin-conjugating enzymes UbcH7 and UbcH8 interact w... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is over-broad for ARIH1. The informative interaction annotations are E2 binding and CRL/SCF association. Reason: Replace generic binding with mechanistically specific E2 or ubiquitin-ligase-complex binding where possible. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. |
| GO:0000151 ubiquitin ligase complex | TAS PMID:10521492 The ubiquitin-conjugating enzymes UbcH7 and UbcH8 interact w... | ACCEPT | Summary: ARIH1 forms functional ubiquitin ligase assemblies with neddylated CRLs; this broad complex annotation captures that E3-ligase-complex context. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md A major current paradigm is that **neddylated CRLs recruit and activate ARIH-family RBR ligases**. Neddylation-induced conformational changes in cullins enable catalysis and can relieve ARIH autoinhibition; ARIH1 then performs the catalytic ubiquitin transfer while the CRL scaffold handles substrate recruitment and E2 positioning. file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. |
| GO:0006511 ubiquitin-dependent protein catabolic process | TAS PMID:10521492 The ubiquitin-conjugating enzymes UbcH7 and UbcH8 interact w... | ACCEPT | Summary: ubiquitin-dependent protein catabolic process is supported by the catalytic role of ARIH1 in ubiquitination and downstream ubiquitin-dependent substrate turnover, especially as a CRL-associated priming E3. Supporting Evidence: file:human/ARIH1/ARIH1-deep-research-falcon.md A major current paradigm is that **neddylated CRLs recruit and activate ARIH-family RBR ligases**. Neddylation-induced conformational changes in cullins enable catalysis and can relieve ARIH autoinhibition; ARIH1 then performs the catalytic ubiquitin transfer while the CRL scaffold handles substrate recruitment and E2 positioning. file:human/ARIH1/ARIH1-deep-research-falcon.md In the best-defined structural/biochemical pathway (SCF–ARIH1 E3–E3 super-assembly), ubiquitin is transferred from **UBE2L3 (UbcH7)** to the **ARIH1 catalytic cysteine** and then to an SCF-bound substrate. |
| GO:0019787 ubiquitin-like protein transferase activity | TAS PMID:10521492 The ubiquitin-conjugating enzymes UbcH7 and UbcH8 interact w... | KEEP AS NON CORE | Summary: ubiquitin-like protein transferase activity is retained as a confirmed secondary ubiquitin-like/ISGylation function: UniProt explicitly states that ARIH1 acts as the ligase involved in ISGylation of EIF4E2, while the dominant core function remains ubiquitin transfer with neddylated CRLs. Reason: Secondary confirmed ubiquitin-like function, not the dominant ARIH1 core activity synthesized from current CRL/RBR literature. Supporting Evidence: file:human/ARIH1/ARIH1-uniprot.txt Acts as the ligase involved in ISGylation of EIF4E2 (PubMed:17289916). file:human/ARIH1/ARIH1-deep-research-falcon.md older literature reported interaction with **UBE2L3 and UBE2L6** |
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