Affinage

ARL6

ADP-ribosylation factor-like protein 6 · UniProt Q9H0F7

Length
186 aa
Mass
21.1 kDa
Annotated
2026-06-09
26 papers in source corpus 14 papers cited in narrative 14 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

ARL6 (BBS3) is an ADP-ribosylation factor-like small GTPase that governs membrane recruitment and ciliary trafficking of the BBSome coat complex, and its loss-of-function causes Bardet-Biedl syndrome (PMID:15258860, PMID:22139371). ARL6 cycles between GDP- and GTP-bound states; only GTP-bound ARL6 binds the BBS1 β-propeller (at blades 1 and 7) to recruit the BBSome to membranes, whereas GDP-bound ARL6 cannot, and single point mutations at the ARL6-GTP–BBS1 interface abolish the interaction and block BBSome import into cilia (PMID:25402481). In knockout mice, ARL6 and the BBSome are mutually dependent for ciliary localization, and ARL6 loss disrupts ciliary localization of melanin-concentrating hormone receptor 1 and impairs retrograde transport of Smoothened, without preventing BBSome assembly (PMID:22139371). The nucleotide cycle is controlled by two Rab-like GTPases: at the basal body IFT22/RABL5 binds and stabilizes ARL6 and, when both are GTP-loaded, recruits the BBSome for coupling to IFT-B1 and ciliary entry (PMID:31953262); inside cilia IFT27/RABL4 binds nucleotide-free ARL6, prevents its aggregation, and promotes its GTP loading to drive BBSome coat assembly and cargo exit (PMID:25443296). A vision-specific long isoform, BBS3L, is selectively required for cone opsin localization and photoreceptor function, distinct from the general ciliary transport role of the canonical isoform (PMID:20333246). ARL6 additionally modulates Wnt signaling in a GTP-dependent manner abolished by BBS mutations (PMID:20207729). BBS-causing mutations act through three mechanisms: impaired GTP binding (e.g., T31R), disruption of the ARL6–BBS1 interface, or protein destabilization and proteasomal degradation (PMID:25402481, PMID:19236846).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2004 High

    Established that ARL6 is a disease gene, linking an Arf-like GTPase to ciliopathy for the first time and motivating mechanistic study of its trafficking role.

    Evidence Comparative genomics and segregation analysis of a homozygous stop mutation in the BBS3 Bedouin kindred

    PMID:15258860

    Open questions at the time
    • Did not define the molecular function of ARL6
    • No mechanism connecting GTPase activity to cilia
  2. 2010 High

    Defined the structural basis of ARL6 nucleotide states and basal body localization, and showed nucleotide-locked variants alter cilium morphology and Wnt signaling, anchoring pathogenesis to nucleotide binding.

    Evidence X-ray crystallography of GTP-bound ARL6 with GTP/GDP-locked variant overexpression and Wnt reporter assays

    PMID:20207729

    Open questions at the time
    • Did not identify the direct effector that ARL6-GTP recruits
    • Wnt mechanism downstream of ARL6 undefined
  3. 2010 High

    Distinguished isoform-specific functions, revealing a vision-dedicated long isoform (BBS3L) required for cone opsin localization separable from general ciliary transport.

    Evidence Isoform-specific zebrafish knockdown/RNA rescue and a Bbs3L-null mouse with photoreceptor defects

    PMID:20333246

    Open questions at the time
    • Molecular basis of isoform-specific opsin trafficking unresolved
    • How BBS3L differs biochemically from BBS3 not established
  4. 2011 High

    Showed ARL6 and the BBSome are mutually dependent for ciliary localization and that ARL6 loss selectively mislocalizes signaling receptors, placing ARL6 as a BBSome trafficking partner rather than an assembly factor.

    Evidence Bbs3 knockout mouse with co-IP, ciliary localization, and receptor trafficking readouts (MCHR1, Smoothened)

    PMID:22139371

    Open questions at the time
    • Did not resolve the direct ARL6–BBSome contact interface
    • Mechanism of retrograde Smoothened transport defect unclear
  5. 2011 Medium

    Pinpointed a residue (A89) required specifically for BBS3L vision function but dispensable for syndromic ciliary transport, refining isoform-specific structure-function.

    Evidence Zebrafish morpholino knockdown with isoform-specific A89V RNA rescue across visual and transport assays

    PMID:21282186

    Open questions at the time
    • Single lab
    • Biochemical consequence of A89V not characterized
  6. 2014 High

    Resolved the atomic mechanism of BBSome recruitment, showing GTP-bound ARL6 binds the BBS1 β-propeller at blades 1 and 7 and that interface mutations (including BBS1 M390R) block ciliary import.

    Evidence Crystal structures of ARL6-GDP, ARL6-GTP, and ARL6-GTP–BBS1 complex from Chlamydomonas with mutagenesis and ciliary import assays

    PMID:25402481

    Open questions at the time
    • Did not define how ARL6 is loaded with GTP at membranes
    • Mammalian validation of the interface relied on ortholog structure
  7. 2014 High

    Identified IFT27/RABL4 as a regulator of ARL6, preventing its aggregation and promoting GTP loading to drive BBSome coat assembly and ciliary exit, defining the intraciliary activation step.

    Evidence Proteomics, biochemical reconstitution, co-IP, and aggregation assays

    PMID:25443296

    Open questions at the time
    • Whether IFT27 acts as a bona fide GEF not biochemically demonstrated here
    • GTP hydrolysis step / GAP unidentified
  8. 2020 High

    Established IFT22/RABL5 as a basal-body stabilizer that, when GTP-loaded together with ARL6, recruits the BBSome for IFT-B1 coupling and ciliary entry, completing the entry-versus-exit regulatory logic.

    Evidence Chlamydomonas functional assays, co-IP, single-particle in vivo imaging, and GTPase activity assays

    PMID:31953262

    Open questions at the time
    • GEF/GAP that toggles ARL6 nucleotide state at the basal body unidentified
    • How BBSome is handed off from IFT22 to IFT trains not structurally resolved
  9. 2009 Medium

    Provided a biochemical classification of BBS mutations, distinguishing selective GTP-binding loss (T31R) from a shared proteasomal destabilization mechanism.

    Evidence In vitro nucleotide-binding assays, mutagenesis, and proteasome inhibitor rescue of mutant expression

    PMID:19236846

    Open questions at the time
    • Single lab without independent replication
    • Degradation pathway components not identified
  10. 2012 Medium

    Demonstrated evolutionary conservation of the ARL6–BBS1 interaction and a microtubule-anchoring vesicular role in trypanosomes, broadening the functional context.

    Evidence RNAi, co-localization, tubulin pulldown, and BBS1 overexpression epistasis in T. brucei

    PMID:22609302

    Open questions at the time
    • Ortholog context limits direct mammalian inference
    • Tubulin interaction not validated in mammalian cells
  11. 1999 Medium

    First showed GTP-dependent membrane association of ARL6 and a candidate SEC61β interaction, an early clue to nucleotide-regulated membrane behavior predating the ciliary model.

    Evidence Yeast two-hybrid screen, co-IP in COS cells, and GTP-γS membrane association assay

    PMID:10508919

    Open questions at the time
    • Functional consequence of SEC61β interaction never established
    • Not integrated into the later ciliary trafficking model
  12. 2016 Low

    Linked ARL6 to ciliogenesis-dependent Hedgehog signaling and tumor cell survival in a cancer context.

    Evidence Immunofluorescence, siRNA knockdown, ciliogenesis, Hedgehog reporter, and proliferation/apoptosis assays in RH30 cells

    PMID:27999656

    Open questions at the time
    • Single-lab knockdown with limited mechanistic dissection
    • Pathway placement of ARL6 in Hedgehog signaling unresolved
  13. 2020 Low

    Connected ARL6 to miR-143-3p regulation and Wnt/β-catenin-dependent osteogenesis, extending its signaling role beyond cilia.

    Evidence Luciferase reporter, miRNA inhibition, ARL6 overexpression, and osteogenesis assays in hBMSCs

    PMID:32522577

    Open questions at the time
    • Mechanistic link of ARL6 to Wnt relies on overexpression/knockdown without direct dissection
    • Independent confirmation lacking

Open questions

Synthesis pass · forward-looking unresolved questions
  • The enzyme(s) that toggle ARL6 between GDP and GTP states at the basal body, and a definitive GAP, remain unidentified, leaving the in vivo nucleotide cycle incompletely closed.
  • No GAP for ARL6 identified
  • GEF activity of IFT27 not biochemically proven
  • How signaling roles (Wnt, Hedgehog) mechanistically depend on ARL6 nucleotide cycling unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 3
Localization
GO:0005815 microtubule organizing center 2 GO:0005886 plasma membrane 2 GO:0005929 cilium 2 GO:0005829 cytosol 1
Pathway
R-HSA-9609507 Protein localization 4 R-HSA-162582 Signal Transduction 2 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
BBS1IFT22IFT27SEC61B
Complex memberships
BBSome

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 ARL6 (BBS3) was identified as the gene mutated in Bardet-Biedl syndrome type 3; a homozygous stop mutation in ARL6 segregates with disease in the original BBS3 Bedouin kindred, establishing ARL6 as an ADP-ribosylation factor-like GTPase causally linked to BBS. Comparative genomic analysis combined with mutation screening and segregation analysis American journal of human genetics High 15258860
2010 Crystal structure of GTP-bound ARL6/BBS3 was determined, revealing ring-like localization at the distal end of basal bodies near the ciliary gate. GTP- or GDP-locked variants of ARL6 influence primary cilium length and abundance. BBS-associated point mutations alter nucleotide binding, providing a structural/mechanistic explanation for pathogenesis. ARL6 also modulates Wnt signaling, and this function is abolished by BBS-associated mutations. X-ray crystallography, overexpression of GTP/GDP-locked variants in vivo (cilium length/abundance assays), functional Wnt signaling assays with BBS point mutants The Journal of biological chemistry High 20207729
2011 In Bbs3 knockout mice, endogenous BBS3 and the BBSome physically interact and depend on each other for their ciliary localization. Loss of Bbs3 does not affect BBSome complex formation but disrupts ciliary localization of melanin concentrating hormone receptor 1 and affects retrograde transport of Smoothened inside cilia. BBS3 and the BBSome associate with membranes independently of each other. Bbs3 knockout mouse model, co-immunoprecipitation, ciliary localization assays, receptor trafficking assays Proceedings of the National Academy of Sciences of the United States of America High 22139371
2010 A vision-specific long isoform of BBS3 (BBS3L) was identified. Zebrafish knockdown of bbs3L impairs visual function and mislocalizes green cone opsin, but does not affect Kupffer's vesicle or melanosome transport (phenotypes caused by bbs3 knockdown). BBS3L RNA, but not BBS3 RNA, rescues vision defects and green opsin localization in zebrafish. A Bbs3L-null mouse presents with disrupted photoreceptor architecture without obesity. Antisense oligonucleotide knockdown in zebrafish, rescue experiments with isoform-specific RNA, Bbs3L-null mouse generation, visual function assays, opsin localization PLoS genetics High 20333246
2014 Crystal structures of ARL6-GDP, ARL6-GTP, and the ARL6-GTP–BBS1 complex from Chlamydomonas reinhardtii were determined. ARL6-GTP binds the BBS1 β-propeller at blades 1 and 7; GDP-bound ARL6 cannot recruit the BBSome to membranes. Single point mutations at the ARL6-GTP–BBS1 interface abolish BBSome interaction and prevent BBSome import into cilia. The BBS1 M390R mutation (responsible for ~30% of BBS cases) fails to interact with ARL6-GTP. X-ray crystallography (ARL6-GDP, ARL6-GTP, ARL6-GTP–BBS1 complex structures), site-directed mutagenesis, ciliary import assays Nature structural & molecular biology High 25402481
2014 The Rab-like GTPase IFT27/RABL4 (a component of IFT-B) directly interacts with nucleotide-free ARL6 upon disengagement from the rest of IFT-B. IFT27 prevents aggregation of nucleotide-free ARL6 in solution and promotes ARL6 activation (GTP loading), BBSome coat assembly, and exit of BBSome and associated cargoes from cilia. Unbiased proteomics, biochemical reconstitution assays, co-immunoprecipitation, in vitro aggregation assays Developmental cell High 25443296
2020 The Rab-like 5 GTPase IFT22/RABL5 binds and stabilizes ARL6 independently of its IFT-B1 association. When both IFT22 and BBS3/ARL6 are in their GTP-bound states, they recruit the BBSome to the basal body for coupling with IFT-B1 subcomplex and subsequent ciliary entry. BBS3/ARL6 interaction with the BBSome is mediated through direct BBS3–BBSome binding. IFT22 is not required for BBSome transport inside cilia, indicating BBSome is transferred from IFT22 to IFT trains at the ciliary base. Functional assays in Chlamydomonas reinhardtii, biochemical co-immunoprecipitation, single particle in vivo imaging, GTPase activity assays Proceedings of the National Academy of Sciences of the United States of America High 31953262
2009 BBS-causing mutations in ARL6 alter guanine nucleotide-binding properties; specifically, T31R selectively abrogates GTP-binding without affecting GDP binding. All BBS mutations tested result in low protein expression that can be restored by proteasome inhibition, indicating mutant ARL6 proteins are destabilized and degraded by the proteasome. In vitro guanine nucleotide-binding assays, site-directed mutagenesis, proteasome inhibitor treatment, protein expression analysis Biochemical and biophysical research communications Medium 19236846
1999 ARL6 protein is predominantly cytosolic but increases membrane association upon GTP-γS exposure. Using yeast two-hybrid screening, ARL6 was found to interact with SEC61β (a subunit of the SEC61 protein-conducting channel); this interaction was confirmed by co-immunoprecipitation in COS cells. Yeast two-hybrid screen, co-immunoprecipitation in COS cells, GTP-γS membrane association assay FEBS letters Medium 10508919
2011 A missense mutation BBS3 A89V rescues transport delays in zebrafish bbs3 morphants (syndromic function intact) but BBS3L A89V fails to rescue vision impairment, demonstrating that A89 is specifically required for the vision/retinal function of the long BBS3L isoform but is dispensable for general ciliary transport function. Zebrafish morpholino knockdown with isoform-specific RNA rescue, visual function assays, melanosome transport assays Human molecular genetics Medium 21282186
2012 In Trypanosoma brucei, TbARL6 localizes to electron-dense vesicles (not cilia) via N-myristoylation. RNAi knockdown of TbARL6 reduces flagellum length. Tubulin was identified as an ARL6 interacting partner (pulldown), suggesting ARL6 anchors vesicles to cytoplasmic microtubules. Overexpression of BBS1 causes translocation of endogenous ARL6 to the flagellar pocket, and BBS1 overexpression combined with ARL6 RNAi has synergistic inhibitory effect on cell growth, indicating conservation of ARL6–BBSome interaction. RNA interference, co-localization, protein pulldown (tubulin interaction), BBS1 overexpression epistasis assay, cell growth assays in T. brucei Biochimica et biophysica acta Medium 22609302
2013 Crystal structure of T. brucei ARL6 (TbArl6) with bound non-hydrolysable GTP analog (GppNp) at 2.0 Å resolution was determined. The structure reveals TbARL6 lacks the key catalytic glutamine for GTP hydrolysis (unlike most small GTPases), has a shorter N-terminus suggesting a different membrane insertion mechanism, and contains two conserved surface patches predicted to mediate protein–protein interactions. X-ray crystallography at 2.0 Å resolution, structural comparison with human ARL6 Protein science Medium 23184293
2016 ARL6 localizes at the base of the primary cilium in RH30 rhabdomyosarcoma cells. Knockdown of ARL6 inhibits ciliogenesis and reduces Hedgehog signaling activity, leading to inhibited proliferation and promoted apoptosis of RH30 cells. Immunofluorescence localization, siRNA knockdown, ciliogenesis assay, Hedgehog signaling reporter assay, proliferation and apoptosis assays Cell & bioscience Low 27999656
2020 miR-143-3p directly targets the 3'-UTR of ARL6 mRNA (confirmed by luciferase reporter assay). Elevated miR-143-3p reduces ARL6 levels and suppresses Wnt/β-catenin signaling (Wnt3a, β-catenin, LEF1, TCF1), inhibiting osteogenic differentiation of hBMSCs. Overexpression of ARL6 blocks cadmium-induced suppression of the Wnt/β-catenin pathway and rescues osteogenesis. Luciferase reporter assay (miR-143-3p binding to ARL6 3'-UTR), miRNA inhibition, lentiviral ARL6 overexpression, Wnt pathway component expression analysis, osteogenesis assay Toxicology letters Low 32522577

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Comparative genomic analysis identifies an ADP-ribosylation factor-like gene as the cause of Bardet-Biedl syndrome (BBS3). American journal of human genetics 180 15258860
2014 The intraflagellar transport protein IFT27 promotes BBSome exit from cilia through the GTPase ARL6/BBS3. Developmental cell 167 25443296
2011 Bardet-Biedl syndrome 3 (Bbs3) knockout mouse model reveals common BBS-associated phenotypes and Bbs3 unique phenotypes. Proceedings of the National Academy of Sciences of the United States of America 115 22139371
2010 Bardet-Biedl syndrome-associated small GTPase ARL6 (BBS3) functions at or near the ciliary gate and modulates Wnt signaling. The Journal of biological chemistry 87 20207729
1999 A novel ADP-ribosylation like factor (ARL-6), interacts with the protein-conducting channel SEC61beta subunit. FEBS letters 69 10508919
2010 Identification and functional analysis of the vision-specific BBS3 (ARL6) long isoform. PLoS genetics 68 20333246
2014 Structural basis for membrane targeting of the BBSome by ARL6. Nature structural & molecular biology 67 25402481
2006 Pathological but not physiological retinal neovascularization is altered in TNF-Rp55-receptor-deficient mice. Investigative ophthalmology & visual science 46 17065527
1998 Canadian Bardet-Biedl syndrome family reduces the critical region of BBS3 (3p) and presents with a variable phenotype. American journal of medical genetics 40 9714014
2011 Functional analysis of BBS3 A89V that results in non-syndromic retinal degeneration. Human molecular genetics 37 21282186
2020 Intraflagellar transport protein RABL5/IFT22 recruits the BBSome to the basal body through the GTPase ARL6/BBS3. Proceedings of the National Academy of Sciences of the United States of America 35 31953262
2018 Contribution of the TNF-α (Tumor Necrosis Factor-α)-TNF-Rp55 (Tumor Necrosis Factor Receptor p55) Axis in the Resolution of Venous Thrombus. Arteriosclerosis, thrombosis, and vascular biology 33 30354252
2000 Characterization, chromosomal localization, and expression during hematopoietic differentiation of the gene encoding Arl6ip, ADP-ribosylation-like factor-6 interacting protein (ARL6). Genomics 28 10995579
2012 A role for the vesicle-associated tubulin binding protein ARL6 (BBS3) in flagellum extension in Trypanosoma brucei. Biochimica et biophysica acta 22 22609302
2009 Biochemical characterization of missense mutations in the Arf/Arl-family small GTPase Arl6 causing Bardet-Biedl syndrome. Biochemical and biophysical research communications 22 19236846
2012 Novel homozygous mutations in the genes ARL6 and BBS10 underlying Bardet-Biedl syndrome. Gene 20 23219996
1996 Tumour necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6) and their soluble receptors (sTNF-alpha-Rp55 and slL-6R) serum levels in systemic lupus erythematodes. Mediators of inflammation 19 18475749
2020 MircoRNA-143-3p regulating ARL6 is involved in the cadmium-induced inhibition of osteogenic differentiation in human bone marrow mesenchymal stem cells. Toxicology letters 16 32522577
2021 Effects of TNFα receptor TNF-Rp55- or TNF-Rp75- deficiency on corneal neovascularization and lymphangiogenesis in the mouse. PloS one 10 33835999
2005 NF-kappaB protects rat ARL-6 hepatocellular carcinoma cells against hydrogen peroxide-induced apoptosis. Cancer biology & therapy 10 16177566
2016 Small GTPase Arl6 controls RH30 rhabdomyosarcoma cell growth through ciliogenesis and Hedgehog signaling. Cell & bioscience 8 27999656
2013 Crystal structure of the small GTPase Arl6/BBS3 from Trypanosoma brucei. Protein science : a publication of the Protein Society 5 23184293
2000 Reciprocal control of apoptosis and proliferation in cultured rat hepatoma arl-6 cells: roles of nutrient supply, serum, and oxidative stress. In vitro cellular & developmental biology. Animal 5 11039496
2022 A Japanese boy with Bardet-Biedl syndrome caused by a novel homozygous variant in the ARL6 gene who was initially diagnosed with retinitis punctata albescens: A case report. Medicine 1 36550847
2025 Machine learning insights into obesity related genes XRCC4 and ARL6 in obstructive sleep apnea. Sleep & breathing = Schlaf & Atmung 0 41082129
2024 Rod-sparing in a bardet-biedl syndrome patient with mutations in the ARL6 gene. Documenta ophthalmologica. Advances in ophthalmology 0 39078565

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