Affinage

ADGB

Androglobin · UniProt Q8N7X0

Length
1667 aa
Mass
189.7 kDa
Annotated
2026-04-28
34 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ADGB (androglobin) is a chimeric globin essential for male fertility, functioning at the intersection of ciliary/flagellar assembly, acrosome biogenesis, and redox biochemistry in spermatogenic cells. The protein contains an N-terminal calpain-like domain, a circularly permuted hexacoordinated globin domain, and an IQ calmodulin-binding motif; calmodulin binding to the IQ motif enhances the nitrite reductase activity of the globin domain (PMID:22115833, PMID:39719941). During spermiogenesis, ADGB interacts with septin 10, CFAP69, SPEF2, TTC29, and CFAP47 to support manchette-mediated sperm head shaping, acrosome development, and flagellum assembly, and its loss in knockout mice or in men with bi-allelic loss-of-function variants causes male infertility with multiple morphological abnormalities of the sperm flagella and acrosome (PMID:35700329, PMID:38385883, PMID:36995441). ADGB is also a component of the ciliary central apparatus C1b/C1f supercomplex, and its transcription is activated by the ciliogenesis regulators FOXJ1 and RFX3 (PMID:34083607, PMID:37158461, PMID:41138754).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2011 High

    Identification of ADGB as a chimeric globin with unprecedented domain architecture—calpain-like, circularly permuted globin, and IQ motif—established it as a new member of the globin superfamily and raised the question of what biological role such a fusion protein serves.

    Evidence Comparative genomics and recombinant expression with UV-vis spectroscopy confirming hexacoordinated heme

    PMID:22115833

    Open questions at the time
    • No in vivo function assigned
    • Enzymatic activity of the globin domain not tested
    • Role of the calpain-like domain unknown
  2. 2021 Medium

    Placement of the ADGB ortholog within the C1b/C1f supercomplex of the ciliary central apparatus linked the protein to motile cilia biology, though its individual contribution to motility was minor in Tetrahymena.

    Evidence Gene deletion in Tetrahymena thermophila with ciliome proteomics and motility assays

    PMID:34083607

    Open questions at the time
    • Mammalian ciliary role not demonstrated
    • Precise position within the C1b/C1f supercomplex unresolved
    • Functional redundancy with other C1b components not tested
  3. 2022 High

    The Adgb knockout mouse demonstrated that ADGB is essential for male fertility, revealing roles in manchette function, acrosome development, and flagellum formation, and identified septin 10 as a direct interactor whose localization depends on ADGB.

    Evidence Knockout mouse with reciprocal co-IP in vivo and in vitro, electron microscopy, and calmodulin-dependent proteolysis assay

    PMID:35700329

    Open questions at the time
    • Calpain-like domain's catalytic competence in vivo not proven
    • Mechanism by which ADGB regulates Sept10 localization and proteolysis remains incomplete
    • Female reproductive or somatic phenotypes not explored
  4. 2023 Medium

    Human genetic and biochemical studies expanded the ADGB interactome to include CFAP69 and SPEF2 and showed that pathogenic ADGB variants disrupt calmodulin binding, directly linking calmodulin interaction to human male infertility.

    Evidence Whole-exome sequencing of infertile men, co-immunoprecipitation, and calmodulin-binding assays

    PMID:36995441

    Open questions at the time
    • Functional consequence of disrupted CaM binding on enzymatic activity not tested in patient-derived cells
    • CFAP69 and SPEF2 binding sites on ADGB not mapped
    • No rescue experiment to confirm causality of identified variants
  5. 2023 Medium

    FOXJ1 was identified as a transcriptional activator of ADGB, placing ADGB downstream of the master ciliogenesis regulatory program.

    Evidence Promoter-luciferase transactivation assay with wild-type and truncating FOXJ1 variant

    PMID:37158461

    Open questions at the time
    • Endogenous ChIP-based confirmation of FOXJ1 binding at the ADGB promoter lacking
    • In vivo requirement of FOXJ1 for ADGB expression not shown
  6. 2024 Medium

    Calmodulin was shown to bind the ADGB globin domain via the IQ motif and enhance its nitrite reductase activity, providing the first defined enzymatic function for androglobin.

    Evidence Recombinant protein fluorescence quenching and UV-vis kinetic assays with structural modeling

    PMID:39719941

    Open questions at the time
    • Physiological relevance of nitrite reductase activity in spermatogenesis not demonstrated
    • No mutagenesis of catalytic residues to confirm mechanism
    • Kinetic parameters under physiological conditions not established
  7. 2024 Medium

    Localization of ADGB to the acrosome and flagella of human and mouse spermatogenic cells was established, and TTC29 and CFAP47 were confirmed as additional interactors, while bi-allelic ADGB loss-of-function variants in patients recapitulated mouse knockout phenotypes.

    Evidence Immunofluorescence, co-immunoprecipitation, whole-exome sequencing, and transmission electron microscopy of patient sperm

    PMID:38385883

    Open questions at the time
    • Direct stoichiometric complex between ADGB and axonemal partners not reconstituted
    • Whether ADGB acts as a structural scaffold versus enzymatic regulator in the flagellum is unresolved
  8. 2025 Medium

    RFX3 was identified as a second transcriptional regulator of ADGB, and overexpression studies linked ADGB to cell motility and ECM remodeling gene programs beyond spermatogenesis.

    Evidence Promoter-luciferase assay, endogenous expression measurement, and RNA-seq of ADGB-overexpressing A549 cells

    PMID:41138754

    Open questions at the time
    • Motility and ECM phenotypes inferred from transcriptomics only, not validated functionally
    • Somatic relevance of ADGB expression outside the testis not confirmed in vivo

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions remain: the catalytic competence and substrates of the calpain-like domain, the physiological role of nitrite reductase activity during spermiogenesis, and whether ADGB plays any functional role in somatic ciliated tissues or non-ciliated contexts.
  • Calpain-like domain substrate specificity and catalytic activity not biochemically defined
  • No structural model of full-length ADGB experimentally validated
  • In vivo significance of NO/nitrite signaling by ADGB unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 2 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005929 cilium 2
Pathway
R-HSA-1474165 Reproduction 3 GO:0005929 cilium 2 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
CALM1CFAP47CFAP69SEPT10SPEF2TTC29
Complex memberships
C1b/C1f ciliary central apparatus supercomplex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 Androglobin (ADGB) was identified as a chimeric protein with a unique modular architecture comprising an N-terminal calpain-like domain homologous to the catalytic domain II of the large subunit of human calpain-7, an internal circularly permuted globin domain, and an IQ calmodulin-binding motif. The recombinantly expressed human globin domain exhibits an absorption spectrum characteristic of hexacoordination of the heme iron atom. Comparative genomics, recombinant protein expression, UV-vis absorption spectroscopy Molecular biology and evolution High 22115833
2022 Adgb knockout male mice are infertile and display impaired maturation of elongating spermatids, abnormal sperm shape, ultrastructural defects in microtubule and mitochondrial organization, multiple flagellar malformations (coiled, bifid, shortened flagella), and erratic acrosomal development. Septin 10 (Sept10) was identified as an interactor of Adgb via immunoprecipitation and mass spectrometry, confirmed by reciprocal co-immunoprecipitation in vivo using testis lysates and in vitro. Absence of Adgb leads to mislocalization of Sept10 in sperm, indicating defective manchette and sperm annulus formation. In vitro data suggest Adgb contributes to Sept10 proteolysis in a calmodulin-dependent manner. Knockout mouse model, immunoprecipitation, mass spectrometry, reciprocal co-immunoprecipitation, electron microscopy, in vitro proteolysis assay eLife High 35700329
2021 In the model ciliate Tetrahymena thermophila, Adgb/androglobin is a component of the C1b/C1f supercomplex of the ciliary central apparatus. Loss of Adgb caused only minor alterations in ciliary motility, whereas loss of Spef2A or Cfap69 led to loss of the entire C1b projection and abnormal vortex motion of cilia. Gene deletion in Tetrahymena thermophila, ciliome proteomics, ciliary motility assays, electron microscopy Scientific reports Medium 34083607
2023 ADGB variants identified in infertile men disrupt the binding of ADGB to calmodulin. Mass spectrometry identified 42 candidate interacting proteins involved in sperm assembly and flagella formation; CFAP69 and SPEF2 were confirmed to bind ADGB by co-immunoprecipitation. Whole-exome sequencing, Sanger sequencing, mass spectrometry, co-immunoprecipitation, electron microscopy Human genetics Medium 36995441
2023 FOXJ1 activates the ADGB promoter in transactivation assays in vitro, placing ADGB as a downstream transcriptional target of FOXJ1 in ciliated cells. A truncating FOXJ1 variant (c.784_799dup; p.Glu267Glyfs*12) fails to activate the ADGB promoter. Transactivation/luciferase reporter assay in vitro, functional variant analysis Human molecular genetics Medium 37158461
2024 Calmodulin (CaM) interacts with the ADGB globin domain via the IQ motif. Using fluorescently labeled CaM mutants (G41C and G114C), greater fluorescence quenching was observed for the N-lobe label (Cys41) due to energy transfer to the heme group, consistent with structural modeling of the Adgb-CaM complex. Binding of CaM enhanced the nitrite reductase activity of Adgb, as shown by UV-vis kinetic studies. Recombinant protein expression, fluorescence quenching assay, AlphaFold3/HDOCK structural modeling, UV-vis kinetic assay RSC chemical biology Medium 39719941
2025 RFX3 regulates ADGB promoter-driven luciferase activity and endogenous ADGB expression levels, identifying RFX3 as a transcriptional regulator of ADGB. Stable overexpression of ADGB in A549 lung cancer cells leads to transcriptomic changes indicating increased cell motility and restructuring of the extracellular matrix. Promoter-luciferase reporter assay, endogenous gene expression measurement, stable overexpression with transcriptome analysis (RNA-seq) Gene Medium 41138754
2024 ADGB localizes to the acrosome and flagella of spermatogenic cells in human and mouse testes. Co-immunoprecipitation confirmed TTC29 and CFAP47 as interacting proteins of ADGB in sperm. Patients with bi-allelic loss-of-function ADGB variants display multiple acrosome and flagellum malformations including acrosome loss, disorganized mitochondrial sheath, and disrupted '9+2' axonemal microtubule structure. Whole-exome sequencing, immunofluorescence localization, co-immunoprecipitation, transmission electron microscopy Andrology Medium 38385883
2026 Co-immunoprecipitation in sperm from a patient with ADGB loss-of-function confirmed TTC29 and CFAP47 as interacting proteins of ADGB. ADGB was found to be highly expressed after puberty in human and mouse testes and localizes to the acrosome and flagella of spermatogenic cells. Co-immunoprecipitation, immunofluorescence staining, Western blot, transmission electron microscopy Sichuan da xue xue bao. Yi xue ban Low 41834962

Source papers

Stage 0 corpus · 34 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Androglobin: a chimeric globin in metazoans that is preferentially expressed in Mammalian testes. Molecular biology and evolution 98 22115833
2013 Bacterial and archaeal globins - a revised perspective. Biochimica et biophysica acta 92 23541529
1988 Abundant expression of herpes simplex virus glycoprotein gB using an adenovirus vector. Virology 75 2834864
2020 Lessons from the post-genomic era: Globin diversity beyond oxygen binding and transport. Redox biology 61 32863222
1990 An adenovirus recombinant that expresses the human cytomegalovirus major envelope glycoprotein and induces neutralizing antibodies. The Journal of infectious diseases 49 2172396
2022 A molecular atlas of the human postmenopausal fallopian tube and ovary from single-cell RNA and ATAC sequencing. Cell reports 45 36543131
1993 Herpes simplex virus (HSV) glycoproteins B and K inhibit cell fusion induced by HSV syncytial mutants. Virology 36 8396800
1999 Recombinant cytomegalovirus glycoprotein gB (UL55) induces an autoantibody response to the U1-70 kDa small nuclear ribonucleoprotein. European journal of immunology 31 10556820
2013 Conservation of globin genes in the "living fossil" Latimeria chalumnae and reconstruction of the evolution of the vertebrate globin family. Biochimica et biophysica acta 26 23360762
1993 Murine cytotoxic T cell response specific for human cytomegalovirus glycoprotein B (gB) induced by adenovirus and vaccinia virus recombinants expressing gB. The Journal of general virology 25 8245869
2022 Androglobin, a chimeric mammalian globin, is required for male fertility. eLife 24 35700329
2014 A general efficient and flexible approach for genome-wide association analyses of imputed genotypes in family-based designs. Genetic epidemiology 21 25044438
2018 Genome-wide association study of maternal genetic effects and parent-of-origin effects on food allergy. Medicine 20 29489655
2003 Mucosal immunization with a replication-deficient adenovirus vector expressing murine cytomegalovirus glycoprotein B induces mucosal and systemic immunity. Vaccine 20 12744900
2021 Composition and function of the C1b/C1f region in the ciliary central apparatus. Scientific reports 19 34083607
2023 ADGB variants cause asthenozoospermia and male infertility. Human genetics 13 36995441
2022 Proteomics Revealed That Mitochondrial Function Contributed to the Protective Effect of Herba Siegesbeckiae Against Cardiac Ischemia/Reperfusion Injury. Frontiers in cardiovascular medicine 13 35872903
2023 Congenital heart defects caused by FOXJ1. Human molecular genetics 12 37158461
2020 Iron metabolic pathways in the processes of sponge plasticity. PloS one 12 32084159
2014 Androglobin knockdown inhibits growth of glioma cell lines. International journal of clinical and experimental pathology 11 24966926
2021 A trimeric capable gB CMV vaccine provides limited protection against a highly cell associated and epithelial tropic strain of cytomegalovirus in guinea pigs. The Journal of general virology 10 33729125
2014 Whole-genome analysis of a patient with early-stage small-cell lung cancer. The pharmacogenomics journal 7 24709692
2002 The genotype of mice influences the autoimmune response to spliceosome proteins induced by cytomegalovirus gB immunization. Clinical and experimental immunology 7 12100018
2024 Whole-exome sequencing identifies ADGB as a novel causative gene for male infertility in humans: from motility to fertilization. Andrology 6 38385883
2024 Globin phylogeny, evolution and function, the newest update. Proteins 4 38192262
2008 Multiple alternating immunizations with DNA vaccine and replication incompetent adenovirus expressing gB of pseudorabies virus protect animals against lethal virus challenge. Journal of microbiology and biotechnology 3 18667863
2025 Complete cross strain protection against congenital cytomegalovirus infection requires a vaccine encoding key antibody (gB) and T-cell (immediate early 1 protein) viral antigens. Frontiers in immunology 2 41200170
2023 CRISPR Activator Approaches to Study Endogenous Androglobin Gene Regulation. Methods in molecular biology (Clifton, N.J.) 2 37039991
2021 Whole-exome sequencing, EGFR amplification and infiltration patterns in human glioblastoma. American journal of cancer research 2 34873478
2024 Calmodulin interacts with androglobin and regulates the nitrite reductase activity. RSC chemical biology 1 39719941
2026 [Whole Exome Sequencing Identified Novel Pathogenic Mutations of ADGB in Patients With Oligoasthenozoospermia]. Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition 0 41834962
2026 Accelerated early weight gain of neonatal puppies from overweight bitches compared to lean dams in spite of similar milk macronutrient composition. Frontiers in nutrition 0 41852679
2025 Complete cross strain protection against congenital cytomegalovirus infection requires a vaccine encoding key antibody (gB) and T-cell (immediate early 1 protein) viral antigens. bioRxiv : the preprint server for biology 0 40611892
2025 Expression analysis of androglobin and its influence on the transcriptome in cancer. Gene 0 41138754