| Feature | Summary for ARL5A | Evidence / notes |
|---|---|---|
| Verified identity | ARL5A is an ARF-like small GTPase of the ARF family; the family is a branch of the Ras superfamily and includes classical ARFs, SARs, ARLs, ARFRP1, and TRIM23. ARL5A is closely related to ARL5B and is typically discussed together with ARL5B in mechanistic studies. | Family-level reviews describe ARL5A as an ARF-family small GTPase and note that ARL5A/ARL5B are among the ARLs retaining an N-terminal amphipathic helix typical of membrane-associated ARF-family proteins (pqac-00000002, pqac-00000008). Evolutionary analyses place Arl5 among ancient eukaryotic ARF-family paralogs, indicating deep conservation (pqac-00000009). |
| Protein family / domains | Small GTPase superfamily, ARF family; expected catalytic core is a P-loop NTPase/small GTP-binding domain with ARF-family features, including conformational switching between GDP- and GTP-bound states and membrane association via an N-terminal amphipathic helix. | General ARF-family structural mechanism and membrane-coupled switching are summarized in recent reviews; these features are directly relevant to ARL5A and consistent with its UniProt domain assignment (pqac-00000002, pqac-00000008, pqac-00000004). |
| Primary molecular function | Molecular switch GTPase. ARL5A binds and hydrolyzes GTP; in the GTP-bound state it recruits effectors to specific membranes rather than catalyzing chemistry on a small-molecule substrate. Its “substrate” as an enzyme is GTP, producing GDP + Pi, while its biological outputs are mediated through effector recruitment. | ARF-family proteins cycle between inactive GDP-bound and active GTP-bound states, with GTP binding exposing effector-binding surfaces; ARL5 studies specifically compare active Q70L and inactive T30N states to define effector binding and function (pqac-00000001, pqac-00000002, pqac-00000010). |
| Immediate upstream regulation | ARL5 recruitment to the trans-Golgi network (TGN) depends on ARFRP1 and the transmembrane protein SYS1; ARFRP1 acts upstream of ARL5 in a Golgi GTPase cascade that coordinates TGN tether recruitment. | ARFRP1/SYS1-dependent recruitment of ARL5 to the TGN is demonstrated genetically and cell biologically; loss of ARFRP1 or SYS1 abolishes ARL5-dependent ARMH3 Golgi localization and disrupts GARP recruitment (pqac-00000001, pqac-00000006, pqac-00000014). |
| Nutrient-responsive regulation | ARL5 also participates in amino-acid-regulated trafficking. Ragulator interacts with ARL5 in an amino-acid-sensitive manner, and Ragulator has been proposed to act as a GEF-like activator for Arl5 during amino-acid sufficiency; glutamine is especially important in disrupting Arl5–Ragulator binding and stimulating retrograde trafficking. | Amino acid sufficiency weakens Arl5–Ragulator association and promotes endosome-to-Golgi trafficking; SLC38A9, v-ATPase, and Ragulator are required, whereas Rag GTPases and mTORC1 are dispensable for this trafficking branch (pqac-00000003, pqac-00000012). |
| Major subcellular localization | Predominantly trans-Golgi network; additional localization to endosomal/lysosomal compartments has been observed, particularly in the context of Ragulator interaction and nutrient-regulated trafficking. | ARL5A shows stronger overlap with TGN46 than with cis/medial Golgi markers, indicating TGN enrichment; Arl5 proteins also localize to peripheral puncta positive for Rab5, Lamp1, and Lamtor1 in live-cell imaging/IF studies (pqac-00000005, pqac-00000012). |
| Major effector proteins | Best-established effectors are the GARP tethering complex and ARMH3; PI4KB is recruited/functionally engaged downstream of ARL5 and ARMH3, and can also be detected as a strong ARL5A/ARL5B interactor in proximity-labeling and co-IP assays. | GARP was previously established as an ARL5 effector for retrograde trafficking; ARMH3 binds active ARL5A/ARL5B and is recruited to the TGN in a SYS1-ARFRP1-ARL5-dependent manner; PI4KB is a strong ARL5A/ARL5B interactor and functional target at the TGN (pqac-00000001, pqac-00000005, pqac-00000006, pqac-00000011). |
| Effector binding specificity | Effector binding is activation-state dependent: active/GTP-like ARL5A or ARL5B preferentially recruits ARMH3 and PI4KB, whereas inactive/GDP-like mutants show reduced or absent interaction. | Mitochondrial relocalization, Y2H, co-IP, and colocalization assays show preference of ARMH3 and PI4KB for active ARL5 forms (pqac-00000005, pqac-00000006, pqac-00000011). |
| Core biological pathway 1 | Endosome-to-TGN retrograde trafficking. ARL5 recruits GARP to the TGN to promote SNARE-dependent fusion of endosome-derived carriers with the TGN. | ARL5 is required for GARP localization to the TGN and for efficient delivery of retrograde cargos such as TGN46, CI-MPR, and Shiga toxin-related cargos in mammalian systems (pqac-00000001, pqac-00000003, pqac-00000014). |
| Core biological pathway 2 | TGN phosphoinositide control: ARL5A/ARL5B promote PI4KB-dependent synthesis of PI4P at the TGN, primarily through recruitment of ARMH3, which activates PI4KB. | Recent work identifies the SYS1-ARFRP1-ARL5-ARMH3 axis as a regulator of PI4KB and the major TGN PI4P pool; earlier proximity-labeling and colocalization studies independently found ARL5A/ARL5B recruit PI4KB to the trans-Golgi (pqac-00000001, pqac-00000005, pqac-00000011). |
| Core biological pathway 3 | Nutrient-linked membrane trafficking. ARL5 connects amino-acid sensing machinery to retrograde traffic independently of canonical Rag/mTORC1 output. | AA-stimulated retrograde trafficking requires SLC38A9, v-ATPase, Ragulator, Arl5, and GARP, linking lysosomal nutrient sensing to Golgi trafficking control (pqac-00000003, pqac-00000012). |
| Downstream cellular consequences | Maintenance of TGN organization and Golgi recycling, efficient protein secretion, recruitment of GOLPH3 via PI4P, and proper glycan modification at the TGN. | ARL5-dependent PI4KB/PI4P signaling contributes to GOLPH3 recruitment and glycan modifications; ARL5A/ARL5B-mediated PI4KB recruitment was also linked to PI4P synthesis and protein secretion in earlier systems-level work (pqac-00000001, pqac-00000005, pqac-00000011). |
| Evidence strength / limitations for Xenopus tropicalis | No organism-specific functional study for Xenopus tropicalis ARL5A was identified in the retrieved literature. Functional annotation for Xenopus ARL5A therefore rests mainly on strong orthology plus conserved domain architecture and detailed mammalian experiments. | The absence of Xenopus-specific primary literature should be stated explicitly; however, conservation of the ARF-family core mechanism and deep evolutionary retention of Arl5 support careful orthology-based inference (pqac-00000009, pqac-00000002, pqac-00000008). |


*Table: This table compiles the main experimentally supported characteristics of ARL5A relevant for functional annotation, including its family assignment, GTPase activity, regulators, localization, effectors, and pathways. It is especially useful because Xenopus-specific literature is sparse, so annotation depends on conserved orthologous evidence from recent mechanistic studies.*