Affinage

ARL6

ADP-ribosylation factor-like protein 6 · UniProt Q9H0F7

Length
186 aa
Mass
21.1 kDa
Annotated
2026-04-28
26 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ARL6 (BBS3) is an Arf-like small GTPase that functions as a GTP-dependent switch controlling BBSome coat complex recruitment to ciliary membranes and regulating ciliary protein trafficking. Structural studies reveal that GTP-bound ARL6 directly binds the BBS1 β-propeller (blades 1 and 7) to recruit the BBSome to membranes for ciliary entry, while IFT22/RABL5 stabilizes ARL6 and cooperates in loading the BBSome onto IFT trains at the basal body, and IFT27/RABL4 activates ARL6 inside cilia to drive BBSome-mediated cargo exit (PMID:25402481, PMID:31953262, PMID:25443296). ARL6 localizes to the distal end of basal bodies near the ciliary gate, where it controls ciliogenesis, retrograde transport of ciliary receptors (MCHR1, Smoothened), and modulates Wnt and Hedgehog signaling (PMID:20207729, PMID:22139371, PMID:27999656). Loss-of-function mutations in ARL6 cause Bardet-Biedl syndrome type 3, with disease-causing mutations disrupting nucleotide binding, protein stability, or the ARL6–BBS1 interface (PMID:15258860, PMID:19236846, PMID:25402481).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1999 Medium

    Establishing ARL6 as a GTP-regulated membrane-associating small GTPase answered the basic question of what type of protein ARL6 encodes and showed it cycles between cytosol and membranes in a nucleotide-dependent manner.

    Evidence Yeast two-hybrid screen, co-IP in COS cells, and membrane fractionation with GTPγS treatment

    PMID:10508919

    Open questions at the time
    • SEC61β interaction not independently confirmed by reciprocal or orthogonal methods
    • GTPase-activating protein (GAP) and guanine nucleotide exchange factor (GEF) for ARL6 not identified
    • physiological relevance of SEC61β interaction unclear
  2. 2004 High

    Identification of ARL6 as the BBS3 gene established that this small GTPase is essential for normal ciliary organ function in humans, linking its molecular activity to a defined ciliopathy.

    Evidence Comparative genomics, mutation screening, and segregation of a homozygous stop mutation in a Bedouin kindred with Bardet-Biedl syndrome

    PMID:15258860

    Open questions at the time
    • Molecular mechanism by which ARL6 loss causes BBS phenotypes unknown
    • no effector proteins identified at this stage
  3. 2010 High

    Crystal structure of GTP-bound ARL6 and localization to the basal body ciliary gate answered how ARL6 is spatially positioned to regulate cilia and demonstrated that its GTP/GDP state controls cilium length, abundance, and Wnt signaling.

    Evidence X-ray crystallography, overexpression of GTP/GDP-locked mutants, cilium assays, and Wnt reporter assays

    PMID:20207729

    Open questions at the time
    • Direct effector through which ARL6 acts on cilia not yet identified
    • mechanism linking ARL6 to Wnt pathway not resolved
  4. 2010 High

    Discovery of the retina-specific BBS3L isoform revealed tissue-specific functions of ARL6, showing that BBS3L is selectively required for photoreceptor opsin trafficking without affecting general ciliary transport.

    Evidence Zebrafish morpholino knockdown with isoform-specific rescue, BBS3L-null mice with retinal phenotype

    PMID:20333246 PMID:21282186

    Open questions at the time
    • Structural basis for isoform-specific function unknown
    • BBS3L-specific interactors not identified
    • whether BBS3L engages BBSome differently than BBS3 not tested
  5. 2011 High

    Demonstration that ARL6 and the BBSome physically interact and co-depend for ciliary localization, with Bbs3 knockout disrupting MCHR1 and Smoothened ciliary trafficking, established ARL6 as a functional partner of the BBSome in receptor transport rather than merely a cilia-localized GTPase.

    Evidence Endogenous co-IP, Bbs3 knockout mouse, immunofluorescence of ciliary receptors, membrane fractionation

    PMID:22139371

    Open questions at the time
    • Whether ARL6 directly contacts BBSome or acts through an intermediate not resolved
    • directionality of ARL6–BBSome dependency (anterograde vs retrograde) unclear
  6. 2011 Medium

    Biochemical characterization of BBS-causing mutations showed that pathogenic variants destabilize ARL6 protein (rescued by proteasome inhibition) or selectively abolish GTP binding, explaining molecular disease mechanisms at the nucleotide-binding level.

    Evidence In vitro GTP/GDP binding assays, site-directed mutagenesis, proteasome inhibitor treatment

    PMID:19236846

    Open questions at the time
    • In vivo protein stability of mutants not assessed
    • whether proteasome-mediated degradation of mutants is a therapeutic target not explored
  7. 2014 High

    Crystal structures of ARL6-GTP bound to the BBS1 β-propeller defined the structural basis for GTP-dependent BBSome recruitment, showing that only GTP-bound ARL6 engages blades 1 and 7 of BBS1, and that the major BBS mutation BBS1-M390R disrupts this interface — answering how ARL6 communicates its activation state to the BBSome coat.

    Evidence X-ray crystallography of ARL6-GDP, ARL6-GTP, and ARL6-GTP–BBS1 complex; interface mutagenesis; ciliary import assays

    PMID:25402481

    Open questions at the time
    • GEF that activates ARL6 to GTP-bound state not identified
    • whether ARL6 remains bound to BBSome during intraciliary transport not known
  8. 2014 High

    Identification of IFT27/RABL4 as an activator of ARL6 that promotes BBSome coat assembly and cargo exit from cilia answered how ARL6 is activated inside cilia and connected intraflagellar transport to BBSome recycling.

    Evidence Unbiased mass spectrometry, biochemical reconstitution, aggregation prevention assays, co-IP

    PMID:25443296

    Open questions at the time
    • Whether IFT27 acts as a direct GEF or stabilizes the nucleotide-free intermediate not fully resolved
    • structural basis of IFT27–ARL6 interaction not determined
  9. 2020 High

    Demonstration that IFT22/RABL5 binds and stabilizes ARL6 and that GTP-bound IFT22 and ARL6 together recruit the BBSome to the basal body for coupling with IFT-B1 resolved how BBSome ciliary entry is initiated and showed that two distinct Rab-like GTPases (IFT22 for entry, IFT27 for exit) regulate ARL6 at different ciliary compartments.

    Evidence Biochemical pull-down, co-IP, single-particle in vivo imaging in Chlamydomonas, IFT22 GTPase assays

    PMID:31953262

    Open questions at the time
    • Whether mammalian IFT22 functions identically to Chlamydomonas ortholog not confirmed
    • temporal ordering of IFT22–ARL6 versus ARL6–BBS1 binding events not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The GEF and GAP that directly catalyze ARL6 nucleotide exchange and hydrolysis remain unidentified, and how ARL6's GTPase cycle is spatially regulated between basal body entry and intraciliary exit compartments is not mechanistically resolved.
  • No GEF or GAP for ARL6 identified
  • structural basis of ARL6–IFT22 and ARL6–IFT27 interactions not determined
  • role of ARL6 in non-ciliary signaling (Wnt, osteogenic differentiation) mechanistically unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 4
Localization
GO:0005929 cilium 4 GO:0005815 microtubule organizing center 2 GO:0005829 cytosol 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 2
Partners
BBS1IFT22IFT27MCHR1SMO
Complex memberships
BBSome (functional partner, not stable subunit)

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 ARL6 (BBS3) was identified as an ADP-ribosylation factor-like small GTPase whose loss-of-function (homozygous stop mutation) causes Bardet-Biedl syndrome type 3, establishing ARL6 as BBS3. Comparative genomic analysis, mutation screening, and segregation analysis in a Bedouin kindred American journal of human genetics High 15258860
1999 ARL6 protein is predominantly cytosolic but its membrane association increases upon GTP-γS exposure; ARL6 interacts with SEC61β (a subunit of the protein-conducting channel), as confirmed by co-immunoprecipitation in COS cells. Yeast two-hybrid screen, co-immunoprecipitation in COS cells, membrane fractionation with GTP-γS treatment FEBS letters Medium 10508919
2010 Crystal structure of GTP-bound ARL6/BBS3 was determined; ARL6 localizes to a ring at the distal end of basal bodies near the ciliary gate; GDP- or GTP-locked variants of ARL6 influence primary cilium length and abundance; ARL6/BBS3 modulates Wnt signaling, a function lost in BBS-associated point mutants due to altered nucleotide binding. X-ray crystallography, overexpression of GTP/GDP-locked variants in vivo, cilium length/abundance assays, Wnt signaling reporter assays, site-directed mutagenesis The Journal of biological chemistry High 20207729
2010 A long isoform of BBS3 (BBS3L), expressed predominantly in the eye, is required for proper photoreceptor function and green cone opsin localization; knockdown of bbs3L in zebrafish causes impaired visual function and opsin mislocalization without affecting Kupffer's vesicle or melanosome transport (unlike the ubiquitous BBS3 isoform); BBS3L-null mice display disrupted photoreceptor architecture without obesity. Antisense oligonucleotide knockdown in zebrafish, rescue experiments with isoform-specific RNA, generation of BBS3L-null mice PLoS genetics High 20333246
2011 Endogenous BBS3/ARL6 and the BBSome physically interact and depend on each other for ciliary localization; loss of Bbs3 does not affect BBSome formation but disrupts normal localization of melanin concentrating hormone receptor 1 (MCHR1) to ciliary membranes and affects retrograde transport of Smoothened inside cilia; both BBSome and BBS3 associate with membranes independently. Co-immunoprecipitation of endogenous proteins, Bbs3 knockout mouse model, immunofluorescence localization of MCHR1 and Smoothened, membrane fractionation Proceedings of the National Academy of Sciences of the United States of America High 22139371
2011 BBS mutations in ARL6 alter guanine nucleotide-binding properties; the T31R mutation selectively abrogates GTP-binding without affecting GDP binding; all BBS mutations result in low protein expression restored by proteasome inhibition, indicating mutant proteins are destabilized and degraded by the proteasome. Biochemical GTP/GDP binding assays, site-directed mutagenesis, proteasome inhibitor treatment, protein expression analysis Biochemical and biophysical research communications Medium 19236846
2014 GTP-bound ARL6 recruits the BBSome to membranes by binding the BBS1 β-propeller at blades 1 and 7; crystal structures of ARL6-GDP, ARL6-GTP, and ARL6-GTP–BBS1 complex explain why only GTP-bound ARL6 can recruit BBSome; single point mutations in the ARL6-GTP–BBS1 interface abolish interaction and prevent BBSome import into cilia; BBS1-M390R (responsible for ~30% of BBS cases) fails to interact with ARL6-GTP. X-ray crystallography (ARL6-GDP, ARL6-GTP, and ARL6-GTP–BBS1 complex structures), mutagenesis, biochemical binding assays, ciliary import assays Nature structural & molecular biology High 25402481
2014 IFT27/RABL4 (a Rab-like GTPase 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; IFT27 promotes BBSome and cargo exit from cilia through ARL6 activation and BBSome coat assembly. Unbiased proteomics (mass spectrometry), biochemical reconstitution assays, co-immunoprecipitation, aggregation prevention assays Developmental cell High 25443296
2020 IFT22/RABL5 binds and stabilizes ARL6/BBS3; when both are in their GTP-bound states, IFT22 and BBS3 recruit the BBSome to the basal body for coupling with IFT-B1 for ciliary entry; BBS3 interacts with the BBSome through direct binding; IFT22 is not required for BBSome transport within cilia, indicating transfer occurs at the ciliary base. Functional assays, biochemical pull-down and co-IP, single-particle in vivo imaging in Chlamydomonas reinhardtii, IFT22 GTPase activity assay Proceedings of the National Academy of Sciences of the United States of America High 31953262
2011 BBS3 A89V mutation is sufficient to rescue retrograde transport defects caused by bbs3 knockdown in zebrafish but BBS3L A89V cannot rescue vision impairment, demonstrating that A89V specifically disrupts retinal/visual function (relevant to ARL6's BBS3L isoform) but not general ciliary trafficking function. Zebrafish bbs3 morpholino knockdown with isoform-specific rescue experiments, melanosome transport assay, visual function assay Human molecular genetics Medium 21282186
2016 ARL6 localizes at the base of primary cilia, controls ciliogenesis, and regulates Hedgehog signaling; knockdown of ARL6 in RH30 rhabdomyosarcoma cells inhibits proliferation and promotes apoptosis through defective ciliogenesis and reduced Hedgehog activity. Immunofluorescence localization, siRNA knockdown, proliferation and apoptosis assays, Hedgehog pathway reporter assay Cell & bioscience Medium 27999656
2020 miR-143-3p directly targets the 3'-UTR of ARL6 mRNA (confirmed by luciferase reporter assay), reducing ARL6 levels and suppressing Wnt/β-catenin signaling (Wnt3a, β-catenin, LEF1, TCF1) and osteogenic differentiation of human bone marrow mesenchymal stem cells; overexpression of ARL6 rescues these effects. Luciferase reporter assay (miRNA target validation), lentiviral ARL6 overexpression, miR-143-3p inhibitor treatment, osteogenic differentiation assay Toxicology letters Medium 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 179 15258860
2014 The intraflagellar transport protein IFT27 promotes BBSome exit from cilia through the GTPase ARL6/BBS3. Developmental cell 166 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 66 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 11 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