Affinage

ADGB

Androglobin · UniProt Q8N7X0

Length
1667 aa
Mass
189.7 kDa
Annotated
2026-06-09
35 papers in source corpus 9 papers cited in narrative 9 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

Androglobin (ADGB) is a chimeric metazoan protein that functions in the assembly of motile cilia/flagella and in spermatid maturation (PMID:35700329, PMID:34083607). Its unique modular architecture combines an N-terminal calpain-like catalytic domain, a circularly permuted hexacoordinated globin domain, and an IQ calmodulin-binding motif (PMID:22115833). Calmodulin binds the IQ motif and enhances the nitrite reductase activity of the heme-binding globin domain (PMID:39719941), and ADGB is in turn required for proper calmodulin localization or stability in sperm (PMID:38385883). In spermatogenesis, ADGB localizes to the acrosome and flagella (PMID:41834962) and is required for sperm head shaping, manchette and annulus formation, and flagellum integrity, acting through interactions with cytoskeletal and ciliary assembly factors including septin 10, CFAP69, SPEF2, TTC29, and CFAP47 (PMID:35700329, PMID:36995441, PMID:41834962); loss of ADGB drives mislocalization of Sept10 and contributes to its proteolysis in a calmodulin-dependent manner (PMID:35700329). In the ciliary central apparatus of Tetrahymena, ADGB associates with the C1b/C1f supercomplex (PMID:34083607). ADGB expression is transcriptionally controlled by the ciliogenic regulators FOXJ1 and RFX3 (PMID:37158461, PMID:41138754). Bi-allelic pathogenic ADGB variants cause male infertility presenting as asthenozoospermia and oligoasthenoteratozoospermia with acrosome, mitochondrial sheath, and axonemal defects (PMID:36995441, PMID:38385883, PMID:41834962).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2011 Medium

    Established that ADGB is a structurally unprecedented chimeric protein, raising the question of how a calpain-like protease, a permuted globin, and a calmodulin-binding motif could function together.

    Evidence Comparative genomics, domain architecture analysis, and UV-vis spectroscopy of the recombinant globin domain

    PMID:22115833

    Open questions at the time
    • Heme redox chemistry and a physiological substrate for the globin domain were not defined
    • Catalytic activity of the calpain-like domain not demonstrated
    • No cellular function or expression context established
  2. 2021 Medium

    Placed ADGB within the ciliary central apparatus, addressing where the protein acts in motile cilia, while showing it is dispensable for the structural integrity of the C1b projection.

    Evidence Gene deletion in Tetrahymena thermophila with cryo-ET/proteomics of ciliary fractions and motility assays

    PMID:34083607

    Open questions at the time
    • Only minor motility phenotype, leaving its functional contribution unclear
    • Mechanism of recruitment to C1b/C1f unknown
    • Ciliate findings not directly mapped to mammalian sperm flagella
  3. 2022 High

    Defined ADGB as essential for spermatid maturation and identified Sept10 as a direct partner, linking ADGB to manchette/annulus formation and to calmodulin-dependent proteolysis.

    Evidence Adgb knockout mouse, IP/MS with reciprocal co-IP in vivo and in vitro, immunofluorescence, electron microscopy

    PMID:35700329

    Open questions at the time
    • Direct demonstration that the calpain-like domain cleaves Sept10 in vivo not shown
    • Whether globin redox state regulates proteolysis unresolved
    • Full substrate repertoire unknown
  4. 2023 Medium

    Connected ADGB to human disease and expanded its interactome, establishing that calmodulin binding and flagellar assembly factors are required for fertility.

    Evidence Whole-exome sequencing of infertile men, Adgb KO mice, MS interactome, co-IP confirming CFAP69 and SPEF2

    PMID:36995441

    Open questions at the time
    • Stoichiometry and hierarchy among CFAP69/SPEF2/ADGB interactions undefined
    • How variants mechanistically abolish CaM binding not resolved at structural level
  5. 2023 Medium

    Identified FOXJ1 as a transcriptional activator of ADGB, embedding ADGB in the master ciliogenic gene-expression program.

    Evidence Transactivation luciferase reporter with a loss-of-function FOXJ1 variant and an in vivo frog epidermis ciliogenesis assay

    PMID:37158461

    Open questions at the time
    • Direct FOXJ1 occupancy of the endogenous ADGB locus not shown
    • Co-regulators and tissue specificity of regulation undefined
  6. 2024 Medium

    Mechanistically linked calmodulin binding to the globin enzymatic activity, showing CaM enhances ADGB nitrite reductase activity via conformational coupling to the heme.

    Evidence Recombinant protein, AlphaFold3/HDOCK modeling, fluorescence quenching with CaM Cys41 mutants, UV-vis nitrite reductase kinetics

    PMID:39719941

    Open questions at the time
    • Structural model is computational, not experimentally solved
    • Physiological relevance of nitrite reductase activity in sperm not demonstrated
    • Link between redox activity and Sept10 proteolysis untested
  7. 2024 Medium

    Extended the human phenotype to acrosome and flagellum malformations and showed ADGB is required for calmodulin abundance in sperm, suggesting a reciprocal ADGB–CaM dependency.

    Evidence Whole-exome/Sanger sequencing, electron microscopy, immunofluorescence, western blot on patient sperm

    PMID:38385883

    Open questions at the time
    • Mechanism by which ADGB stabilizes or localizes CaM not defined
    • Single-lab patient cohort
  8. 2025 Medium

    Added RFX3 as a second ciliogenic transcriptional regulator of ADGB and raised a non-sperm role in cell motility and ECM remodeling.

    Evidence Promoter-luciferase reporter, CRISPRa endogenous induction, stable overexpression transcriptomics in A549 cells

    PMID:41138754

    Open questions at the time
    • Functional significance of the cancer-cell motility/ECM signature unestablished
    • Whether RFX3 acts directly or via the cilia program unclear
  9. 2026 Medium

    Refined ADGB subcellular localization to acrosome and flagella and added TTC29 and CFAP47 to the flagellar interactome, consolidating ADGB as a hub for axoneme and mitochondrial sheath organization.

    Evidence Immunofluorescence localization, co-IP for TTC29 and CFAP47, transmission EM, western blot, whole-exome sequencing

    PMID:41834962

    Open questions at the time
    • Whether interactions are direct or scaffold-mediated not resolved
    • Order of assembly events ADGB participates in unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the calpain-like protease, globin redox chemistry, and calmodulin sensing are integrated into a single coordinated activity governing flagellar/ciliary assembly remains unresolved.
  • No experimental structure of full-length ADGB or its complexes
  • In vivo proteolytic substrates beyond Sept10 unconfirmed
  • Physiological role of globin nitrite reductase activity in sperm not demonstrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0016491 oxidoreductase activity 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005856 cytoskeleton 2 GO:0005929 cilium 2
Pathway
R-HSA-1474165 Reproduction 3 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) is a chimeric protein with a unique modular architecture comprising an N-terminal calpain-like domain homologous to catalytic domain II 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, domain architecture analysis, recombinant protein expression and UV-vis spectroscopy Molecular biology and evolution Medium 22115833
2022 Adgb knockout mice display male infertility with impaired spermatid maturation, abnormal sperm shape, and ultrastructural defects in microtubule and mitochondrial organization. Immunoprecipitation and mass spectrometry identified septin 10 (Sept10) as an interactor of Adgb, confirmed by reciprocal co-immunoprecipitation both in vivo (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-IP, immunofluorescence, electron microscopy eLife High 35700329
2021 In Tetrahymena thermophila, Adgb/androglobin localizes to the C1b/C1f supercomplex of the ciliary central apparatus. Deletion of Adgb caused only minor alterations in ciliary motility, whereas loss of other C1b/C1f subunits (Spef2A or Cfap69) caused loss of the entire C1b projection and abnormal cilia motion. Gene deletion in Tetrahymena, cryo-ET/proteomics of ciliary fractions, motility assays Scientific reports Medium 34083607
2023 Pathogenic variants in ADGB disrupt binding of ADGB to calmodulin, causing asthenozoospermia and male infertility. Mass spectrometry identified 42 candidate interacting proteins involved in sperm assembly, flagella formation, and sperm motility; CFAP69 and SPEF2 were confirmed to bind ADGB by co-immunoprecipitation. Whole-exome sequencing, Adgb knockout mice, mass spectrometry, co-immunoprecipitation, electron microscopy Human genetics Medium 36995441
2023 FOXJ1 activates the ADGB promoter in transactivation assays in vitro, establishing ADGB as a downstream transcriptional target of FOXJ1 in ciliated cells. A truncating FOXJ1 variant (p.Glu267Glyfs*12) failed to activate the ADGB promoter. Transactivation luciferase reporter assay, in vivo frog epidermis ectopic cilia assay Human molecular genetics Medium 37158461
2024 Calmodulin (CaM) interacts with ADGB via its IQ motif, and this interaction enhances the nitrite reductase activity of the ADGB heme-binding globin domain. Fluorescence quenching experiments using CaM mutants labeled at Cys41 (N-lobe) showed greater energy transfer to the heme group upon ADGB binding, consistent with predicted structural models of the Adgb-CaM complex. Recombinant protein expression, AlphaFold3/HDOCK structural prediction, fluorescence quenching assay with CaM mutants, UV-vis kinetic assay for nitrite reductase activity RSC chemical biology Medium 39719941
2024 Bi-allelic deleterious ADGB variants in infertile men cause multiple acrosome and flagellum malformations in spermatozoa. Functional assays revealed structural defects associated with dysregulation of ADGB and multiple spermatogenesis proteins. CaM deficiency (but normal PLCζ) was detected in sperm from ADGB-deficient patients, suggesting ADGB is required for calmodulin localization or stability in sperm. Whole-exome sequencing, Sanger sequencing, electron microscopy, immunofluorescence, western blot Andrology Medium 38385883
2025 RFX3 regulates ADGB promoter-driven luciferase activity and endogenous ADGB expression levels, identifying RFX3 as a transcriptional regulator of ADGB. Stable ADGB overexpression in A549 lung cancer cells caused transcriptomic changes indicative of increased cell motility and extracellular matrix remodeling. Promoter-luciferase reporter assay, CRISPRa endogenous expression induction, stable overexpression with transcriptome analysis Gene Medium 41138754
2026 ADGB localizes to the acrosome and flagella of spermatogenic cells in humans and mice, with high expression after puberty. Co-immunoprecipitation experiments confirmed TTC29 and CFAP47 as interacting proteins of ADGB. Compound heterozygous pathogenic ADGB mutations cause oligoasthenoteratozoospermia with acrosome loss, disorganized mitochondrial sheath, and disrupted axonemal '9+2' microtubule structure. Immunofluorescence localization, co-immunoprecipitation, transmission electron microscopy, western blot, whole-exome sequencing Sichuan da xue xue bao. Yi xue ban Medium 41834962

Source papers

Stage 0 corpus · 35 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 100 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 76 2834864
2020 Lessons from the post-genomic era: Globin diversity beyond oxygen binding and transport. Redox biology 64 32863222
2022 A molecular atlas of the human postmenopausal fallopian tube and ovary from single-cell RNA and ATAC sequencing. Cell reports 50 36543131
1990 An adenovirus recombinant that expresses the human cytomegalovirus major envelope glycoprotein and induces neutralizing antibodies. The Journal of infectious diseases 49 2172396
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
2022 Androglobin, a chimeric mammalian globin, is required for male fertility. eLife 25 35700329
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
2018 Genome-wide association study of maternal genetic effects and parent-of-origin effects on food allergy. Medicine 21 29489655
2014 A general efficient and flexible approach for genome-wide association analyses of imputed genotypes in family-based designs. Genetic epidemiology 21 25044438
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
2022 Proteomics Revealed That Mitochondrial Function Contributed to the Protective Effect of Herba Siegesbeckiae Against Cardiac Ischemia/Reperfusion Injury. Frontiers in cardiovascular medicine 15 35872903
2020 Iron metabolic pathways in the processes of sponge plasticity. PloS one 14 32084159
2023 ADGB variants cause asthenozoospermia and male infertility. Human genetics 13 36995441
2023 Congenital heart defects caused by FOXJ1. Human molecular genetics 12 37158461
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
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 3 41200170
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
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
2026 Parent-of-origin effects in sheep: impact on the data fit, explanatory power of the model and theoretical accuracy of the breeding values. Scientific reports 0 42056368
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

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