Affinage

ARL3

ADP-ribosylation factor-like protein 3 · UniProt P36405

Length
182 aa
Mass
20.5 kDa
Annotated
2026-06-09
50 papers in source corpus 28 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ARL3 is a ciliary small GTPase that functions as a nucleotide-state-dependent release factor governing the delivery and retrieval of lipid-modified and other cargoes at the primary cilium (PMID:22085962, PMID:22960633, PMID:26814127). Its activity is set by a regulatory cycle: ARL13B is the guanine nucleotide exchange factor that activates ARL3, with GEF activity mediated by its G-domain plus a C-terminal helix and impaired by Joubert syndrome mutations (PMID:26551564, PMID:28487361), while BART acts as a co-GEF that, together with ARL13B, efficiently activates ARL3 at physiological GTP:GDP ratios and stabilizes the GTP-bound state until effector binding (PMID:33438581); RP2 serves as the cognate GAP, binding ARL3 in a nucleotide- and myristoylation-dependent manner through an interface defined by RP2 disease residues (PMID:12417528, PMID:16472755). In the GTP-bound state, ARL3 allosterically displaces myristoylated cargo (e.g., NPHP3) from UNC119 — uniquely among Arf-family GTPases tested, accelerating cargo release by orders of magnitude while leaving its own N-terminal amphipathic helix surface-bound — and releases prenylated phototransduction cargo (PDE6, GRK1) from PrBPδ/PDEδ, thereby targeting lipidated proteins to the cilium (PMID:22085962, PMID:22960633, PMID:10518933, PMID:26814127, PMID:26936825). ARL3 also extends beyond lipidated-cargo release to ciliary trafficking machinery: it coordinates IFT-A/IFT-B reassociation alongside ARL13B (PMID:20530210), mediates BBSome retrieval across the transition zone (PMID:36129685, PMID:37579161), facilitates unloading of the outer dynein arm adaptor ODA16 from IFT trains (PMID:39231220, PMID:39880089), and localizes ciliary-tip kinesins Kif7 and Kif17 in cooperation with RP2 (PMID:28444310). The spatial ARL3·GTP gradient generated by this regulatory cascade is required for photoreceptor ciliogenesis, lipidated-cargo transport, and nuclear positioning, and dominant ARL3 variants that distort this gradient cause retinal disease (PMID:26814127, PMID:36598133). Variants impairing the ARL3–ARL13B interface (ARL3-Arg149; ARL13B Joubert mutations) reduce ciliary targeting of INPP5E and NPHP3, linking ARL3 dysfunction to ciliopathy (PMID:26551564, PMID:30269812). Distinct from its ciliary roles, ARL3 has reported functions in cytokinesis and microtubule association (PMID:16525022, PMID:12417528), dynein–dynactin dissociation (PMID:25342295), planar cell polarity during skin development (PMID:30952667), and as a binding partner stabilizing STAT3 signaling and ERα (PMID:27048653, PMID:41047477).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1999 High

    Establishing whether ARL3 has a defined effector addressed how this GTPase, with anomalously weak nucleotide binding, could function; identifying PDEδ as a GTP-specific partner gave ARL3 a biochemical output.

    Evidence Yeast two-hybrid, fluorescence spectroscopy, Co-IP and nucleotide kinetics defining PDEδ as a GTP-specific effector that stabilizes ARL3·GTP

    PMID:10518933

    Open questions at the time
    • Did not define the cellular cargo released via PDEδ
    • Physiological GEF/GAP that set the GTP state not yet known
  2. 2000 High

    Resolving how ARL3 toggles between nucleotide states required structural detail; the GDP structure revealed the N-terminal helix and a magnesium-independent binding mode predicting conformational coupling to GTP loading.

    Evidence 1.7 Å crystal structure of murine ARL3-GDP plus fluorescent nucleotide binding kinetics

    PMID:11188688

    Open questions at the time
    • No GTP-bound structure in this study
    • Functional consequence of the predicted helix release untested
  3. 2002 Medium

    Connecting ARL3 to disease and cytoskeleton, RP2 was identified as a direct nucleotide- and myristoylation-dependent partner, and ARL3 was localized to microtubules and the photoreceptor connecting cilium.

    Evidence Co-IP, microtubule co-purification from bovine brain, drug-induced relocalization, and photoreceptor localization

    PMID:12417528

    Open questions at the time
    • RP2 catalytic (GAP) role not yet demonstrated biochemically
    • Mechanism of microtubule association unresolved
  4. 2006 High

    Two questions were addressed: the structural basis of RP2–ARL3 binding and whether ARL3 controls cytokinesis; RP2 structure mapped a disease-correlated ARL3 interface and siRNA implicated ARL3 in mitotic microtubule regulation.

    Evidence RP2 crystal structure with mutagenesis of disease residues; siRNA knockdown in HeLa with cytokinesis and tubulin-acetylation readouts

    PMID:16472755 PMID:16525022

    Open questions at the time
    • Cytokinesis study is Medium-confidence and from a single lab
    • How ARL3 mechanistically controls midbody microtubules unresolved
  5. 2010 High

    Whether ARL3 integrates with IFT regulation was tested genetically; ARL-3 depletion suppressed arl-13 ciliogenesis defects via an HDAC6-dependent restoration of IFT-A/B binding, placing ARL3 in a ciliary regulatory circuit with ARL13.

    Evidence C. elegans epistasis, ciliary EM, and IFT subcomplex binding assays

    PMID:20530210

    Open questions at the time
    • Indirect, genetic placement; no biochemical ARL3 substrate defined here
    • Relationship of this IFT role to lipidated cargo release unclear
  6. 2011 High

    The central mechanistic question — what ARL3·GTP does — was answered: ARL3-GTP allosterically displaces myristoylated cargo from UNC119, defining ARL3 as a lipidated-cargo release factor required for ciliary targeting.

    Evidence Proteomics, Co-IP, UNC119 pocket mutagenesis, and siRNA with ciliary localization readout across worm and mammalian cells

    PMID:22085962

    Open questions at the time
    • Structural basis of the allosteric displacement not yet shown
    • Generality across cargo classes (prenylated) not addressed
  7. 2012 High

    How ARL3 achieves cargo specificity was resolved structurally: crystal structures of ARL3 vs ARL2 with UNC119 showed only ARL3 widens the myristoyl pocket to accelerate release ~1000-fold despite similar binding affinities.

    Evidence Crystal structures of ARL3·GppNHp and ARL2·GppNHp with UNC119a plus quantitative cargo-release kinetics

    PMID:22960633

    Open questions at the time
    • Did not establish the in vivo GEF generating ARL3·GTP
    • Prenylated-cargo release mechanism via PDEδ not structurally addressed
  8. 2014 Medium

    ARL3's interaction network was extended beyond cilia: it was implicated in TGN-to-cilium polycystin trafficking and in dynactin release from dynein, broadening its proposed trafficking roles.

    Evidence Yeast two-hybrid/Co-IP for Rabep1/GGA1/ARL3 module; Co-IP, microtubule pull-down, single-molecule tracking and KD for dynein-dynactin dissociation

    PMID:25342295 PMID:25405894

    Open questions at the time
    • Both are single-lab; mechanistic integration with the GTPase cycle unclear
    • Direct vs indirect roles not fully separated
  9. 2015 High

    Identifying ARL13B as the ARL3 GEF closed the activation loop and linked Joubert syndrome to ARL3 dysregulation; BARTL1 was concurrently defined as an N-helix-reading ARL3·GTP partner controlling ARL3 ciliary localization.

    Evidence In vitro GEF assays with Joubert variant mutagenesis and cell-based ARL3·GTP measurement; structural/biochemical characterization of BARTL1 binding the ARL3 N-terminal motif

    PMID:26455799 PMID:26551564

    Open questions at the time
    • Whether ARL13B GEF activity alone is sufficient at physiological nucleotide ratios untested
    • BARTL1 downstream function not yet defined
  10. 2016 High

    In vivo validation in photoreceptors established ARL3 as a cargo displacement factor for both myristoylated and prenylated proteins required for ciliogenesis, while a partner-discovery effort linked ARL3 to STAT3 signaling.

    Evidence Conditional and dominant-active ARL3-Q71L mice with retinal Co-IP, AAV rescue and ERG; Q71L PrBPδ sequestration; yeast two-hybrid/Co-IP/KD for STAT3

    PMID:26814127 PMID:26936825 PMID:27048653

    Open questions at the time
    • STAT3 role is Medium-confidence and mechanistically separate from cilia
    • How the same GTPase coordinates two lipid-modification classes in vivo not fully resolved
  11. 2017 High

    Purified-protein reconstitution confirmed ARL13B GEF activity and its atypically low intrinsic GTPase rate, and ARL3/RP2 were shown to position ciliary-tip kinesins Kif7 and Kif17.

    Evidence Recombinant ARL13B biochemistry with JS mutagenesis; Co-IP and siRNA in cilia, patient fibroblasts and iPSC optic cups for Kif7/Kif17

    PMID:28444310 PMID:28487361

    Open questions at the time
    • Kif7/Kif17 study is Medium-confidence, single lab
    • Whether kinesin positioning depends on canonical cargo-release activity unclear
  12. 2018 Medium

    Human genetics directly tied the ARL3–ARL13B interface to disease: ARL3-Arg149 variants impaired GEF interaction and reduced ciliary INPP5E and NPHP3, establishing the activation step as clinically critical.

    Evidence Exome sequencing, biochemical interaction assays, and ciliary-cargo immunofluorescence in patient cells

    PMID:30269812

    Open questions at the time
    • Single-lab functional characterization
    • Dominant vs recessive mechanism not fully dissected
  13. 2019 Medium

    ARL3 was shown to be required for planar spindle orientation and PCP-component distribution in skin stem cells, extending its function to polarized trafficking in development.

    Evidence Conditional knockout in mouse epidermis with spindle-orientation and Celsr1/Vangl2/Frizzled6 localization analyses

    PMID:30952667

    Open questions at the time
    • Mechanistic link to the cargo-release activity not established
    • Endosomal trafficking role inferred, not directly demonstrated
  14. 2021 High

    Resolving why ARL13B alone activates ARL3 weakly, BART was defined as a co-GEF that with ARL13B efficiently activates ARL3 at physiological nucleotide ratios and stabilizes ARL3·GTP until effector binding.

    Evidence In vitro GEF assays at physiological GTP:GDP, binding assays, and live-cell ciliary imaging

    PMID:33438581

    Open questions at the time
    • In vivo requirement for BART co-GEF activity not tested genetically here
    • Spatial regulation of the BART/ARL13B cascade within cilia not resolved
  15. 2022 Medium

    Two studies extended ARL3 to BBSome retrieval and protein stabilization: ARL3·GTP was shown to recruit shed BBSomes for transition-zone passage, and USP48 was reported to stabilize ARL3/UNC119a.

    Evidence Chlamydomonas genetics and live-cell IFT/BBSome imaging; Co-IP, localization and stability assays for USP48

    PMID:36129685 PMID:36293380

    Open questions at the time
    • USP48 finding is Low-confidence single Co-IP
    • Whether BBSome retrieval is conserved mechanistically in mammals untested here
  16. 2023 High

    The ciliary ARL3·GTP gradient was shown to be the functional unit: in photoreceptors it governs nuclear positioning, and a RABL2·GDP GEF step plus ARL13B-driven cystogenesis defined upstream and downstream gradient regulation.

    Evidence Transgenic ARL3-D67V/Y90C mouse gradient manipulation and rescue; Chlamydomonas RABL2 GEF/IFT imaging; Arl13b-R79Q knock-in epistasis in Pkd1 mice (preprint)

    PMID:36598133 PMID:37579161

    Open questions at the time
    • Cystogenesis epistasis is a preprint
    • Molecular link between gradient and nuclear migration machinery undefined
  17. 2024 Medium

    ARL3's role in motor-arm assembly was defined: active ARL3·GTP unloads the outer-dynein-arm adaptor ODA16 from IFT trains, with conservation to human DAW1, and was reported to displace Shulin/DNAAF9 from packaged ODAs.

    Evidence Trypanosoma genetic depletion, Co-IP and conservation analysis for ODA16; in vitro reconstitution/mutagenesis for DNAAF9 (preprint)

    PMID:39231220

    Open questions at the time
    • DNAAF9 study is a preprint
    • Whether ODA unloading and lipidated-cargo release use the same GTP-driven mechanism not directly compared
  18. 2025 Medium

    The ODA16 unloading mechanism was refined structurally and ARL3 was assigned non-ciliary chaperone/export roles, including ERα stabilization and ubiquitin-cargo export with CFAP36.

    Evidence In silico/biochemical mapping of the ODA16 β-propeller interface; Co-IP and ubiquitination mapping for ERα/USP10; structural and depletion studies of CFAP36/ARL3 (preprint)

    PMID:39880089 PMID:41047477

    Open questions at the time
    • ERα and CFAP36 roles are single-lab/preprint and mechanistically distinct
    • How a ciliary GTPase performs nuclear-receptor chaperone function unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single GTP-state switch coordinates ARL3's diverse outputs — lipidated-cargo release, BBSome retrieval, ODA unloading, kinesin positioning, and non-ciliary stabilization roles — and whether these reflect one unifying biochemical activity or distinct effector-specific mechanisms.
  • No unified structural model linking cargo-release to IFT-machinery unloading
  • Non-ciliary roles (STAT3, ERα, dynactin) not integrated with the GTPase cycle
  • In vivo necessity of individual interactions across tissues incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Localization
GO:0005929 cilium 4 GO:0005856 cytoskeleton 2 GO:0005635 nuclear envelope 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-9609507 Protein localization 3 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-1266738 Developmental Biology 1
Partners
ARL13BBARTODA16PDE6DRP2STAT3UNC119

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 ARL3-GTP acts as a release factor for myristoylated cargo from UNC119b: ARL3-GTP binding to UNC119b allosterically displaces myristoylated cargo (e.g., NPHP3), and this cycle—together with the ARL3 GAP RP2—is required for targeting myristoylated proteins to the primary cilium. UNC119b myristoyl-binding activity is essential for this process. Proteomic identification, co-immunoprecipitation, directed mutagenesis of UNC119 hydrophobic pocket, structural modeling, siRNA knockdown with ciliary localization readout Genes & development High 22085962
2006 ARL3 localizes to centrosomes, mitotic spindles, midzones, midbodies, and cilia. Knockdown of ARL3 by siRNA causes changes in cell morphology, increased acetylation of alpha-tubulin, failure of cytokinesis, and increased binucleated cells, indicating ARL3 binds microtubules in a regulated manner to control specific aspects of cytokinesis. siRNA knockdown in HeLa cells, immunofluorescence, cell morphology and cytokinesis phenotype analysis, microtubule co-localization Molecular biology of the cell Medium 16525022
2010 In C. elegans, depletion of ARL-3 partially suppresses ciliogenesis defects in arl-13 mutants by indirectly restoring binding between IFT subcomplexes A and B via an HDAC6 deacetylase-dependent pathway, placing ARL-3 as a coordinator of IFT regulation alongside ARL-13. Genetic epistasis in C. elegans double mutants, electron microscopy of ciliary ultrastructure, IFT subcomplex binding assays The Journal of cell biology High 20530210
2015 ARL13B (mutated in Joubert syndrome) is the guanine nucleotide exchange factor (GEF) for ARL3; its GEF activity is mediated by the G-domain plus an additional C-terminal helix, and the switch regions of ARL13B interact with ARL3 during nucleotide exchange. Overexpression of ARL13B increases ARL3·GTP levels in cells, while Joubert syndrome patient mutations in ARL13B impair GEF activity and ARL3 activation. In vitro GEF assay, biochemical characterization, mutagenesis of Joubert syndrome variants, overexpression in mammalian cells with ARL3·GTP level measurement eLife High 26551564
2002 RP2 interacts directly with ARL3 in a nucleotide- and myristoylation-dependent manner. ARL3 co-localizes with microtubules in HeLa cells (enhanced by taxol stabilization) and co-purifies with microtubules from bovine brain; following nocodazole treatment ARL3 relocalizes to the nuclear membrane. In photoreceptors, ARL3 and cofactor C localize predominantly to the connecting cilium. Co-immunoprecipitation, immunofluorescence, microtubule co-purification from bovine brain, nocodazole/taxol drug treatment, patient cell line analysis Human molecular genetics Medium 12417528
2014 PC1/PC2 ciliary trafficking involves a Rabep1/GGA1/ARL3-dependent mechanism at the trans-Golgi network: Rabep1 couples the polycystin complex to a GGA1/ARL3-based ciliary trafficking module for TGN-to-cilium targeting. Yeast two-hybrid screening, candidate approach, co-immunoprecipitation, ciliary localization assays Nature communications Medium 25405894
2012 Crystal structures of ARL3·GppNHp and ARL2·GppNHp in complex with UNC119a reveal that only ARL3 allosterically displaces myristoylated cargo from UNC119, accelerating cargo release by three orders of magnitude. Contrary to other GTP-bound Arf family members, the N-terminal amphipathic helix of ARL3·GppNHp is not displaced but remains surface-bound, inducing widening of the myristoyl binding pocket. ARL2 and ARL3 bind UNC119 with similar affinities but only ARL3 causes cargo release. Crystal structure determination, in vitro cargo release kinetics assay, comparison of ARL2 vs ARL3 specificity The EMBO journal High 22960633
1999 ARL3 interacts with PDE delta (PDEδ, the delta subunit of cGMP phosphodiesterase) in a GTP-specific manner; ARL3 has unusually low affinity for GTP (KD ~48 µM) and PDEδ stabilizes the GTP-bound form of ARL3 by strongly decreasing GTP dissociation rate, indicating PDEδ is an effector of ARL3 and may provide a novel nucleotide exchange mechanism. Yeast two-hybrid, fluorescence spectroscopy, co-immunoprecipitation, nucleotide binding kinetics FEBS letters High 10518933
2016 In rod photoreceptors, ARL3 functions as a cargo displacement factor for lipidated phototransduction proteins (myristoylated and prenylated), and in retina-specific knockouts it is required for ciliogenesis and axoneme formation. Rod-specific expression of dominant-active ARL3-Q71L causes accumulation of prenylated proteins (PDE6, GRK1) in the inner segment, with specific interaction between ARL3-Q71L and prenyl binding protein δ (PrBPδ) demonstrated in retina. AAV-mediated ARL3-EGFP expression rescues ciliogenesis. Conditional knockout mice (rod- and retina-specific Cre), transgenic dominant-active ARL3-Q71L mice, immunofluorescence, co-immunoprecipitation in retina, AAV rescue experiment, ERG The Journal of biological chemistry High 26814127
2017 Biochemical characterization of purified recombinant murine ARL13B confirms it functions as a GEF for ARL3, with measurable nucleotide exchange activity. ARL13B is atypical with very low intrinsic GTPase activity. Joubert syndrome missense mutations in ARL13B alter these biochemical properties. Purified recombinant protein, solution-based nucleotide binding assay, GTPase assay, GEF activity assay, mutagenesis of JS variants The Journal of biological chemistry High 28487361
2006 Crystal structure of human RP2 at 2.1 Å resolution shows it consists of an N-terminal beta helix and a C-terminal ferredoxin-like domain. The N-terminal 34 residues and beta helix domain of RP2 are required for interaction with ARL3. RP2 patient missense mutations R118H and E138G show drastically reduced affinity for ARL3, correlating ability to bind ARL3 with disease causation. X-ray crystallography, binding affinity measurements, mutagenesis of disease-associated residues Structure High 16472755
2018 ARL3 missense variants replacing Arg149 impair interaction with the GEF ARL13B, resulting in reduced ciliary localization of INPP5E and NPHP3, establishing ARL3-Arg149 as critical for ARL13B-mediated GEF activity and downstream ciliary cargo targeting. Exome sequencing, biochemical interaction assays, immunofluorescence of ciliary cargo localization in patient cells American journal of human genetics Medium 30269812
2017 ARL3 and its GAP RP2 interact with ciliary tip kinesins Kif7 and Kif17. ARL3 and RP2 mediate localization of GFP-Kif17 to the cilia tip and show competitive binding with Kif17 complexes. siRNA-mediated loss of RP2 or ARL3 reduces Kif7 at cilia tips, confirmed in patient-derived fibroblasts and iPSC optic cups lacking RP2. Co-immunoprecipitation, siRNA knockdown, immunofluorescence in cilia, patient-derived fibroblasts and iPSC-derived optic cups Human molecular genetics Medium 28444310
2000 The 1.7 Å crystal structure of murine ARL3-GDP reveals: (1) the N-terminal extension folds into an elongated loop anchored hydrophobically on the protein surface, predicted to release upon GTP binding; (2) tight GDP binding occurs without magnesium ion due to a lysine residue substituting the canonical Mg2+ site; (3) a beta-sheet register shift upon GTP binding is predicted. These structural features distinguish ARL3/ARL2 from Arf proteins. X-ray crystallography at 1.7 Å, fluorescent mGDP kinetic binding experiments Structure High 11188688
2014 GTP-bound ARL3 (ARL3-Q71L) and dynein light chain LC8 induce dissociation of dynactin from dynein. Immunoprecipitation and microtubule pull-down assays show ARL3(Q71L) facilitates dynactin detachment. Live-cell imaging with quantum dot-conjugated proteins demonstrates ARL3(Q71L)-mediated dynactin release from dynein-dynactin complex. Knockdown of ARL3 causes abnormal localizations of dynein, dynactin, and related organelles. Co-immunoprecipitation, microtubule pull-down assay, quantum dot single-molecule tracking, siRNA knockdown with organelle localization readout Nature communications Medium 25342295
2016 ARL3 is identified as a novel STAT3-binding partner; ARL3 recognizes the DNA-binding domain and C-terminal region of STAT3. siRNA-mediated reduction of ARL3 decreases IL-6-induced tyrosine phosphorylation, nuclear accumulation, and transcriptional activity of STAT3. Yeast two-hybrid screening, co-immunoprecipitation in vivo, siRNA knockdown with STAT3 phosphorylation and nuclear accumulation readout The Journal of biological chemistry Medium 27048653
2015 CCDC104/BARTL1 is an ARL3 binding partner containing a BART-like domain that recognizes an LLxILxxL motif at the N-terminal amphipathic helix of ARL3·GTP. This N-terminal helix interaction is also crucial for ciliary localization of ARL3 itself. Biochemical binding assays, structural analysis of BARTL1 domain, mutagenesis of ARL3 N-terminal motif, ciliary localization experiments Structure Medium 26455799
2021 BART functions as a co-GEF for ARL3: at physiological GTP:GDP ratios, ARL13B alone weakly activates ARL3-GDP, but BART (interacting with nucleotide-free ARL3) in concert with ARL13B efficiently activates ARL3. BART also binds ARL3·GTP to inhibit GTP dissociation and stabilize the active G-protein; ARL3 effector binding then releases BART. Live-cell imaging shows BART accesses the primary cilium and colocalizes with ARL13B. In vitro GEF/nucleotide exchange assays at physiological GTP:GDP concentrations, biochemical binding assays, live-cell imaging with fluorescent proteins eLife High 33438581
2022 ARL3 mediates BBSome ciliary retrieval: ARL3·GDP binds the ciliary membrane and, following nucleotide exchange to ARL3·GTP (promoted by the ciliary GEF cascade), ARL3·GTP detaches from the ciliary membrane, binds retrograde IFT train-shed PLD-laden BBSomes at the proximal ciliary region above the transition zone, and recruits them to pass the transition zone for ciliary retrieval via diffusion. This mechanism underlies why ARL3-related Joubert syndrome shares phenotypes with Bardet-Biedl syndrome. Chlamydomonas genetics, live-cell imaging of IFT and BBSome dynamics, functional domain analysis, epistasis experiments The Journal of cell biology Medium 36129685
2016 Dominant-active ARL3-Q71L in rod photoreceptors causes sequestration of prenyl binding protein δ (PrBPδ) as demonstrated by specific co-immunoprecipitation in retina, leading to defective trafficking of prenylated proteins (PDE6, GRK1) to the outer segment and rod cell death. ARL3 also has a novel role in photoreceptor nuclear migration. Transgenic mouse expressing dominant-active ARL3-Q71L under rod-specific promoter, co-immunoprecipitation in retinal tissue, immunofluorescence, ERG Human molecular genetics Medium 26936825
2019 ARL3 is required for planar spindle orientation of mouse basal stem cells during skin development. Loss of ARL3 reduces planar cell divisions and increases perpendicular divisions, expanding progenitors and disrupting epithelial integrity. ARL3 loss disrupts planar polarized distribution of PCP components Celsr1 and Vangl2, and Frizzled6 asymmetry, suggesting ARL3 regulates polarized endosomal trafficking of PCP components. Conditional knockout in mouse epidermis, immunofluorescence of spindle orientation and PCP components, quantitative analysis of cell division angles Development Medium 30952667
2024 ARL3 facilitates ODA16 unloading from the IFT complex: active ARL3·GTP binds ODA16 (a known IFT cargo adapter for outer dynein arms) and dissociates ODA16 from the IFT complex. Depletion of ARL3 causes ODA16 accumulation in cilia and defects in axonemal assembly. This interaction is conserved between Trypanosoma brucei and human (HsDAW1/ARL3), and disease variants in HsDAW1 alter these interactions. Genetic depletion in Trypanosoma brucei, co-immunoprecipitation, biochemical interaction assays, conservation analysis with human proteins Science advances Medium 39231220
2023 Dominant ARL3 mutations (D67V with constitutive activity; Y90C as fast-cycling) create an aberrant ARL3·GTP gradient in mouse rod photoreceptors, causing displaced nuclear phenotype. Removing or restoring the ciliary ARL3·GTP gradient is sufficient to rescue the nuclear migration defect, demonstrating that the ARL3·GTP ciliary gradient is required for proper photoreceptor nuclear positioning during retinal development. Transgenic mouse models expressing ARL3-D67V and ARL3-Y90C in rods, multiple genetic strategies to manipulate ARL3·GTP gradient, immunofluorescence for nuclear position eLife High 36598133
2022 USP48 (a deubiquitinating enzyme) interacts with ARL3 and UNC119a in the retina; a pool of endogenous USP48 localizes to the basal body. USP48 interaction stabilizes ARL3 and UNC119a protein levels through distinct mechanisms. Co-immunoprecipitation, immunofluorescence for subcellular localization, protein stability assays International journal of molecular sciences Low 36293380
2016 GTP hydrolysis in the ARL3-RP2 complex is catalyzed with glutamine 71 (Gln71) of ARL3 actively participating in the reaction mechanism; QM/MM computational modeling reveals two reaction intermediates specific to ARL3-RP2 distinct from Ras-GAP, with Arg118 of RP2 serving as a catalytic arginine and Glu138 positioning it for catalysis. QM/MM computational modeling based on crystal structure of ARL3-RP2 complex with substrate analog The journal of physical chemistry B Low 27043216
2025 ARL3 stabilizes ERα as a novel chaperone via direct binding, and ARL3 maintains ERα stability by upregulating USP10, which removes K48/K63-linked polyubiquitin chains from ERα at the K252 site. Genetic ablation of ARL3 induces ERα ubiquitination-dependent degradation. Co-immunoprecipitation for direct binding, ubiquitination assays identifying K48/K63 linkage and K252 site, genetic ablation with protein stability readout Advanced science Medium 41047477
2023 In Chlamydomonas, RABL2·GTP (cycling through cilia via IFT as an IFT-B1 cargo) dissociates from retrograde IFT trains above the transition zone, converts to RABL2·GDP, and acts as a GEF for ARL3·GDP, thereby generating ARL3·GTP that detaches from the ciliary membrane and recruits PLD-laden BBSomes for transition zone passage. RABL2·GDP then exits cilia as a BBSome cargo. Chlamydomonas genetics, live-cell imaging of IFT dynamics, GEF activity assays, epistasis analysis Proceedings of the National Academy of Sciences Medium 37579161
2025 Integrative in silico and biochemical analyses show that ARL3 directly binds ODA16 via its C-terminal β-propeller face, the same surface used by IDA3, and that ARL3 and IDA3 binding to ODA16 dissociates ODA16 from IFT46 (which binds the opposite face), likely through an allosteric mechanism, facilitating ODA release from IFT. AlphaPulldown in silico screening, structural modeling, biochemical binding assays, biophysical assays with Chlamydomonas and human proteins The Journal of biological chemistry Medium 39880089
2024 DNAAF9 (human Shulin) preferentially binds active ARL3·GTP state; GTP-loaded ARL3 can access, bind, and displace Shulin (DNAAF9) from the packaged ODA-Shulin complex, proposing a mechanism whereby ARL3·GTP inside cilia displaces Shulin to allow ODA motor activation. Proteomics, in vitro reconstitution, mutagenesis, biochemical and structural studies bioRxivpreprint Medium
2025 A complex of CFAP36 (previously CCDC104/BARTL1) and ARL3 binds polyubiquitinated proteins and links them to retrograde IFT trains for export from cilia; CFAP36 uses coincidence detection to bind two IFT subunits accessible only in retrograde trains. Depleting CFAP36 accumulates K63-linked ubiquitin in cilia and disrupts Hedgehog signaling. Multidisciplinary structural and biochemical approach, co-immunoprecipitation, functional depletion with Hedgehog signaling readout bioRxivpreprint Medium
2025 ARL13B's GEF activity for ARL3, specifically localized to cilia, is a key mechanism driving Pkd1-dependent renal cystogenesis: mice expressing ARL13B with a mutation critical for ARL3 GEF activity (R79Q) show suppressed PKD1-dependent cysts, renal fibrosis, injury, and reduced β-catenin/cyclin D1 levels. Knock-in mouse alleles (Arl13b-V358A and Arl13b-R79Q) in Pkd1-deficient adult mouse model, renal morphology analysis, cystic index, BUN measurement, fibrosis staining, immunofluorescence, protein level analysis bioRxivpreprint Medium

Source papers

Stage 0 corpus · 50 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 to the primary cilium. Genes & development 190 22085962
2006 Arl2 and Arl3 regulate different microtubule-dependent processes. Molecular biology of the cell 135 16525022
2010 The small GTPases ARL-13 and ARL-3 coordinate intraflagellar transport and ciliogenesis. The Journal of cell biology 134 20530210
2015 A G-protein activation cascade from Arl13B to Arl3 and implications for ciliary targeting of lipidated proteins. eLife 128 26551564
2002 Localization in the human retina of the X-linked retinitis pigmentosa protein RP2, its homologue cofactor C and the RP2 interacting protein Arl3. Human molecular genetics 106 12417528
2014 Ciliary membrane proteins traffic through the Golgi via a Rabep1/GGA1/Arl3-dependent mechanism. Nature communications 97 25405894
2012 Structural basis for Arl3-specific release of myristoylated ciliary cargo from UNC119. The EMBO journal 93 22960633
1999 The delta subunit of rod specific cyclic GMP phosphodiesterase, PDE delta, interacts with the Arf-like protein Arl3 in a GTP specific manner. FEBS letters 85 10518933
2016 Arf-like Protein 3 (ARL3) Regulates Protein Trafficking and Ciliogenesis in Mouse Photoreceptors. The Journal of biological chemistry 81 26814127
2020 N6 -methyladenosine modification of circular RNA circ-ARL3 facilitates Hepatitis B virus-associated hepatocellular carcinoma via sponging miR-1305. IUBMB life 78 33372396
2006 Crystal structure of the human retinitis pigmentosa 2 protein and its interaction with Arl3. Structure (London, England : 1993) 72 16472755
2018 ARL3 Mutations Cause Joubert Syndrome by Disrupting Ciliary Protein Composition. American journal of human genetics 68 30269812
2017 Arl3 and RP2 regulate the trafficking of ciliary tip kinesins. Human molecular genetics 53 28444310
2000 Structural and biochemical properties show ARL3-GDP as a distinct GTP binding protein. Structure (London, England : 1993) 52 11188688
2017 Biochemical characterization of purified mammalian ARL13B protein indicates that it is an atypical GTPase and ARL3 guanine nucleotide exchange factor (GEF). The Journal of biological chemistry 48 28487361
2012 Arl3 and RP2 mediated assembly and traffic of membrane associated cilia proteins. Vision research 46 22884633
2016 Sorting of lipidated cargo by the Arl2/Arl3 system. Small GTPases 40 27806215
2016 De Novo Occurrence of a Variant in ARL3 and Apparent Autosomal Dominant Transmission of Retinitis Pigmentosa. PloS one 38 26964041
2016 ARL3 regulates trafficking of prenylated phototransduction proteins to the rod outer segment. Human molecular genetics 37 26936825
2015 The Interaction of CCDC104/BARTL1 with Arl3 and Implications for Ciliary Function. Structure (London, England : 1993) 27 26455799
2021 Autosomal Recessive Rod-Cone Dystrophy Associated With Compound Heterozygous Variants in ARL3 Gene. Frontiers in cell and developmental biology 22 33748123
2021 ARL3 activation requires the co-GEF BART and effector-mediated turnover. eLife 21 33438581
2019 Dominant ARL3-related retinitis pigmentosa. Ophthalmic genetics 20 30932721
2017 The Arl3 and Arl1 GTPases co-operate with Cog8 to regulate selective autophagy via Atg9 trafficking. Traffic (Copenhagen, Denmark) 18 28627726
2022 ARL3 mediates BBSome ciliary turnover by promoting its outward movement across the transition zone. The Journal of cell biology 17 36129685
2019 Homozygous Variant in ARL3 Causes Autosomal Recessive Cone Rod Dystrophy. Investigative ophthalmology & visual science 15 31743939
2021 A Novel ARL3 Gene Mutation Associated With Autosomal Dominant Retinal Degeneration. Frontiers in cell and developmental biology 13 34485303
2016 A New STAT3-binding Partner, ARL3, Enhances the Phosphorylation and Nuclear Accumulation of STAT3. The Journal of biological chemistry 13 27048653
2014 Arl3 and LC8 regulate dissociation of dynactin from dynein. Nature communications 13 25342295
2018 Binary Function of ARL3-GTP Revealed by Gene Knockouts. Advances in experimental medicine and biology 12 29721959
2016 The Function of Arf-like Proteins ARL2 and ARL3 in Photoreceptors. Advances in experimental medicine and biology 12 26427472
2023 Disrupting the ciliary gradient of active Arl3 affects rod photoreceptor nuclear migration. eLife 10 36598133
2024 ARL3 GTPases facilitate ODA16 unloading from IFT in motile cilia. Science advances 9 39231220
2022 The Deubiquitinating Enzyme USP48 Interacts with the Retinal Degeneration-Associated Proteins UNC119a and ARL3. International journal of molecular sciences 8 36293380
2018 ARL3 subcellular localization and its suspected role in autophagy. Biochimie 8 30227171
2019 The ciliary GTPase Arl3 maintains tissue architecture by directing planar spindle orientation during epidermal morphogenesis. Development (Cambridge, England) 7 30952667
2025 Piperine inhibits the proliferation of colorectal adenocarcinoma by regulating ARL3-mediated endoplasmic reticulum stress. Biomolecules & biomedicine 6 38972051
2024 Mechanisms underlying morphological and functional changes of cilia in fibroblasts derived from patients bearing ARL3T31A and ARL3T31A/C118F mutations. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 6 38457249
2016 Reaction Mechanism of Guanosine Triphosphate Hydrolysis by the Vision-Related Protein Complex Arl3-RP2. The journal of physical chemistry. B 6 27043216
2025 ARL3 Enhances ERα Stability via USP10 Deubiquitination to Promote Endocrine Resistance and Drive Mitochondrial Metabolic Reprogramming in HR+ Breast Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 5 41047477
2021 Mechanism of Guanosine Triphosphate Hydrolysis by the Visual Proteins Arl3-RP2: Free Energy Reaction Profiles Computed with Ab Initio Type QM/MM Potentials. Molecules (Basel, Switzerland) 5 34208932
2020 Expression patterns of ciliopathy genes ARL3 and CEP120 reveal roles in multisystem development. BMC developmental biology 5 33297941
2005 Assay and functional analysis of the ARL3 effector RP2 involved in X-linked retinitis pigmentosa. Methods in enzymology 5 16413292
2025 A novel recurrent ARL3 variant c.209G > A p.(Gly70Glu) causes variable non-syndromic dominant retinal dystrophy with defective lipidated protein transport in human retinal stem cell models. Human molecular genetics 4 40037334
2023 RABL2 promotes the outward transition zone passage of signaling proteins in cilia via ARL3. Proceedings of the National Academy of Sciences of the United States of America 4 37579161
2025 Integrative in silico and biochemical analyses demonstrate direct Arl3-mediated ODA16 release from the intraflagellar transport machinery. The Journal of biological chemistry 3 39880089
2021 Transcript pattern analysis of Arf-family genes in the phytopathogen Fusarium oxysporum f. sp. lycopersici reveals the role of Arl3 in the virulence. Antonie van Leeuwenhoek 3 34338933
2024 Mitochondrial functional impairment in ARL3-mutation related rod-cone dystrophy. FASEB bioAdvances 2 39512837
2025 Spatial regulation of ARL3 and GSF-mediated lipidated cargo trafficking in the primary cilium. FEBS letters 1 40836900
2026 A Novel Heterozygous ARL3 Variant in Non-Syndromic Retinitis Pigmentosa: Clinical and Functional Characterization. International journal of molecular sciences 0 41828587

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