Affinage

ZPBP2

Zona pellucida-binding protein 2 · UniProt Q6X784

Length
338 aa
Mass
38.7 kDa
Annotated
2026-06-11
39 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZPBP2 is a testis-expressed protein required for acrosome biogenesis and sperm morphogenesis during spermiogenesis: mice lacking Zpbp2 are subfertile, develop aberrant acrosomal membrane invaginations, and produce dysmorphic sperm with impaired ability to penetrate the zona pellucida (PMID:17664285). Its proper acrosomal distribution depends on PRSS54, which physically interacts with ZPBP2 alongside the acrosomal proteins ZPBP1, ACRBP, and ZP3R; loss of PRSS54 mislocalizes ZPBP2 without changing its abundance, placing ZPBP2 downstream of PRSS54-organized acrosomal architecture (PMID:35863763). On the human sperm surface ZPBP2 is found within high-molecular-weight complexes with affinity for homologous zonae pellucidae, including association with the chaperonin-containing TCP-1 (CCT) complex, and antibodies against complex subunits block sperm-zona binding (PMID:21672535). Beyond the male germline, the Zpbp2 locus has a distinct somatic role: deletion of the gene region attenuates airway hyperresponsiveness in a sex-dependent manner and reshapes lung sphingolipid/ceramide profiles (PMID:29536159), in part by lowering expression of the neighboring gene Ormdl3 (PMID:32273303), and the locus harbors cis-regulatory elements that influence circadian expression of the clock gene Nr1d1 (PMID:31560728). ZPBP2 expression is itself controlled by sex- and age-dependent DNA methylation of its promoter, which modulates allele-specific expression (PMID:23546690, PMID:28241063).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2003 Low

    Establishing what ZPBP2 is at the sequence level was the first step: in silico characterization defined it as a secreted-type glycoprotein with a zona pellucida binding protein homologous domain co-expressed with ZPBP1 in testis, framing a candidate role in fertilization.

    Evidence in silico gene identification, domain and cDNA characterization, expression analysis

    PMID:12883658

    Open questions at the time
    • Computational prediction only; no direct functional experiment
    • Secretion and glycosylation not experimentally verified
    • ZPBH-domain biochemical activity undefined
  2. 2007 High

    Whether ZPBP2 has a non-redundant in vivo function was answered by a knockout showing it is required for acrosome biogenesis: null males are subfertile with acrosomal membrane invaginations, dysmorphic sperm, and impaired zona penetration.

    Evidence Zpbp2 knockout mouse with fertility assays, sperm morphology, and ultrastructural analysis

    PMID:17664285

    Open questions at the time
    • Molecular mechanism linking ZPBP2 to acrosomal membrane shaping unresolved
    • Direct binding partners within the acrosome not identified in this study
    • Whether the defect is structural or signaling not distinguished
  3. 2011 Medium

    To define how ZPBP2 participates in sperm-zona recognition, proteomics placed it within high-molecular-weight sperm-surface complexes (including the CCT complex) that bind homologous zonae, with antibody inhibition implicating these complexes functionally.

    Evidence blue native PAGE, ESI-MS proteomics, western blot, antibody inhibition of sperm-zona binding

    PMID:21672535

    Open questions at the time
    • Direct ZPBP2-CCT contact not demonstrated by reciprocal methods
    • Stoichiometry and architecture of the complex unknown
    • Functional inhibition attributed to complex, not ZPBP2 specifically
  4. 2013 Medium

    The discovery that ZPBP2 promoter methylation differs by sex and age opened a regulatory axis, linking the locus to control of neighboring 17q12-q21 gene expression.

    Evidence bisulfite sequencing of ZPBP2 promoter in blood stratified by sex and age, plus TDT genetic association

    PMID:23546690

    Open questions at the time
    • Causal effect of methylation on ZPBP2 transcription not shown here
    • Mechanism connecting promoter methylation to neighboring gene expression undefined
    • Tissue specificity beyond blood not addressed
  5. 2017 Medium

    Two studies extended ZPBP2 biology: one proposed an HA-binding (hyaladherin) function via a Link-like domain, and another established that promoter demethylation directly upregulates ZPBP2 in an allele-dependent manner.

    Evidence HA affinity panning with LC-MS/MS and structural homology; 5-aza-dC treatment of human cell lines with bisulfite sequencing and allelic expression analysis

    PMID:28241063 PMID:29126140

    Open questions at the time
    • HA-binding claim rests on single affinity method with expected hyaladherins absent (Low confidence)
    • Functional consequence of HA binding for fertilization not tested
    • Identity of the cis-elements driving allelic methylation response unknown
  6. 2018 Medium

    A somatic role emerged when Zpbp2 deletion was shown to attenuate airway hyperresponsiveness in females and to reshape lung sphingolipid/ceramide pools, with lung resistance correlating with S1P levels.

    Evidence Zpbp2 knockout mouse, methacholine AHR challenge, lung sphingolipid lipidomics, correlation analysis

    PMID:29536159

    Open questions at the time
    • Whether the effect is from ZPBP2 protein or deletion of cis-regulatory DNA not separated
    • Basis of the sex-specific phenotype unexplained
    • Direct molecular link between ZPBP2 and sphingolipid enzymes missing
  7. 2019 Medium

    The locus was tied to circadian regulation: deletion of the Zpbp2 region altered tissue- and time-dependent expression of the clock gene Nr1d1 and enhanced Ormdl3 in liver, identifying cis-regulatory elements within the locus.

    Evidence Zpbp2 KO mouse, diurnal RT-qPCR profiling of Nr1d1 and Ormdl3 across tissues and time points

    PMID:31560728

    Open questions at the time
    • Specific regulatory elements not mapped
    • Whether ZPBP2 transcript/protein mediates the effect vs deleted DNA unresolved
    • Mechanism of cross-regulation of Nr1d1 unknown
  8. 2020 Medium

    Dissecting which asthma phenotypes ZPBP2 controls showed that lower Ormdl3 in KO mice reduced AHR but did not prevent inflammation, mucus, or ceramide changes, separating ZPBP2-dependent from ZPBP2-independent effects.

    Evidence Zpbp2 KO mouse in HDM allergic asthma model, RT-qPCR for Ormdl3, AHR, histology, ceramide measurement

    PMID:32273303

    Open questions at the time
    • Mechanism by which ZPBP2 locus modulates Ormdl3 not defined
    • Direct molecular intermediary between Ormdl3 and AHR unestablished
    • Generalizability beyond the HDM model untested
  9. 2022 Medium

    The acrosomal interaction network was clarified by identifying PRSS54 as a binding partner whose loss mislocalizes ZPBP2 (and ZPBP1, ACRBP, ZP3R) without altering its levels, placing ZPBP2 downstream of PRSS54-organized acrosomal architecture.

    Evidence Co-immunoprecipitation of PRSS54 with ZPBP2; Prss54 KO mouse with immunofluorescence localization in sperm/testis

    PMID:35863763

    Open questions at the time
    • Direct vs indirect nature of the PRSS54-ZPBP2 interaction not resolved
    • Structural basis of acrosomal targeting unknown
    • Whether ZPBP2 mislocalization alone explains the fertility phenotype untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved whether the somatic respiratory, sphingolipid, and circadian phenotypes reflect a functional role of the ZPBP2 protein itself or the removal of cis-regulatory DNA within the locus, and the biochemical activity of the ZPBH domain in the acrosome is still undefined.
  • No experiment separates ZPBP2 protein function from locus cis-regulatory effects
  • No defined molecular/enzymatic activity for the ZPBH domain
  • No structural model of ZPBP2 in any complex

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Pathway
R-HSA-1474165 Reproduction 3
Partners
ACRBPPRSS54ZP3RZPBP1
Complex memberships
CCT (chaperonin-containing TCP-1) sperm-surface complex

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 ZPBP2 (Zpbp2) plays a structural role during spermiogenesis; male mice null for Zpbp2 are subfertile, exhibit aberrant acrosomal membrane invaginations, and produce dysmorphic sperm with reduced ability to penetrate the zona pellucida, demonstrating that ZPBP2 is required for proper acrosome biogenesis. Zpbp2 knockout mouse model with fertility assays, sperm morphology analysis, and ultrastructural studies Molecular and cellular biology High 17664285
2011 ZPBP2 is a component of high-molecular-weight protein complexes on the human sperm surface that display affinity for homologous zonae pellucidae; specifically, ZPBP2 was identified as a component of the chaperonin-containing TCP-1 (CCT) complex on sperm, and antibodies against complex subunits inhibited sperm binding to zona-intact oocytes. Blue native PAGE, electrospray ionization mass spectrometry proteomics, western blotting, antibody inhibition of sperm-zona binding Developmental biology Medium 21672535
2017 ZPBP2 contains a Link-like hyaluronic acid (HA)-binding domain and partitions exclusively into the HA-binding fraction from human sperm lysates, suggesting it may function as a hyaladherin in sperm-oocyte interaction. Protein affinity panning with HA substrate, LC-MS/MS proteomics, western blotting, structural homology analysis via PDBsum Molecular human reproduction Low 29126140
2018 Deletion of the mouse Zpbp2 gene attenuates airway hypersensitivity (AHR) in female but not male mice in the absence of allergic sensitization, and is associated with significantly lower levels of sphingosine-1-phosphate (S1P) and very long-chain ceramides (VLCCs), and higher levels of long-chain ceramides in female KO lungs; lung resistance correlated with lung S1P levels, suggesting Zpbp2 regulates AHR through ceramide/sphingolipid metabolism in a sex-dependent manner. Zpbp2 knockout mouse model, methacholine challenge (AHR measurement), lipidomics (sphingolipid profiling of lung, liver, spleen, plasma), Pearson correlation analysis Mammalian genome Medium 29536159
2019 Zpbp2 and Ormdl3 expression are regulated by the circadian clock in a tissue-specific fashion in mice; deletion of the Zpbp2 genomic region alters the expression profile of the core clock gene Nr1d1 in lungs and ileum in a time-dependent manner, and is associated with enhanced Ormdl3 expression in liver, indicating the Zpbp2 locus contains cis-regulatory elements that influence circadian clock gene expression. Zpbp2 KO mouse model, diurnal gene expression profiling (RT-qPCR) across tissues, comparison of Nr1d1 and Ormdl3 expression between KO and WT at multiple time points PloS one Medium 31560728
2020 Zpbp2 KO mice express lower levels of Ormdl3 mRNA than WT mice; in allergic asthma (HDM model), lower Ormdl3 expression in Zpbp2 KO mice was associated with lower AHR, but KO mice were not protected from inflammatory cell infiltration, mucus accumulation, or aberrant ceramide levels, indicating ZPBP2 influences Ormdl3 expression and AHR but not all allergic inflammatory phenotypes. Zpbp2 KO mouse model, HDM-induced allergic asthma model, RT-qPCR (Ormdl3 expression), AHR measurement, histological analysis, ceramide level measurement The Journal of pharmacology and experimental therapeutics Medium 32273303
2022 PRSS54 interacts with acrosomal proteins ZPBP1, ZPBP2, ACRBP, and ZP3R in testis and sperm; loss of PRSS54 disrupts the distribution of ZPBP2 (and other acrosomal proteins) in testis and sperm without affecting their protein levels, placing ZPBP2 as a downstream target of PRSS54-mediated acrosomal organization. Co-immunoprecipitation (interaction of PRSS54 with ZPBP2), Prss54 KO mouse model, immunofluorescence localization of ZPBP2 in KO vs WT Biology of reproduction Medium 35863763
2013 DNA methylation at a regulatory region within the ZPBP2 gene promoter shows statistically significant sex-specific and age-dependent differences, with higher methylation in adult males vs boys and sex-specific differences between males and females; this region was also identified as containing functionally important polymorphisms influencing expression of neighboring 17q12-q21 genes. Bisulfite sequencing methylation assay of ZPBP2 promoter region in blood samples stratified by sex and age, TDT genetic association test Human genetics Medium 23546690
2017 Treatment of airway epithelial cells (NuLi-1) with the DNA methyltransferase inhibitor 5-aza-dC causes upregulation of ZPBP2 expression accompanied by a decrease in promoter methylation (8-13% change sufficient to cause substantial RNA level changes); allelic expression of ZPBP2 is modulated by DNA methylation, with different alleles responding differently to demethylation treatment. 5-aza-2'-deoxycytidine treatment of human cell lines (NuLi-1, 293T, MCF-7), RT-qPCR expression analysis, bisulfite sequencing of ZPBP2 promoter methylation, allelic expression analysis PloS one Medium 28241063
2003 ZPBP2 (originally named ZPBPL/ZPBP-like) encodes a secreted-type glycoprotein with a zona pellucida binding protein homologous (ZPBH) domain containing 15 conserved cysteine residues; the gene consists of seven exons and the protein shares 34.8% amino acid identity with ZPBP1 (a type 2 transmembrane protein), with both co-expressed in testis. In silico gene identification, bioinformatics domain analysis, cDNA characterization, expression analysis International journal of molecular medicine Low 12883658

Source papers

Stage 0 corpus · 39 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease. American journal of human genetics 245 19732864
2007 Loss of zona pellucida binding proteins in the acrosomal matrix disrupts acrosome biogenesis and sperm morphogenesis. Molecular and cellular biology 209 17664285
2012 Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study. American journal of human genetics 156 22464253
2016 17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells. Nature communications 104 27848966
2018 GWAS in childhood acute lymphoblastic leukemia reveals novel genetic associations at chromosomes 17q12 and 8q24.21. Nature communications 87 29348612
2011 Involvement of multimeric protein complexes in mediating the capacitation-dependent binding of human spermatozoa to homologous zonae pellucidae. Developmental biology 87 21672535
2011 Genome-wide association studies for discovery of genes involved in asthma. Respirology (Carlton, Vic.) 75 21276132
2003 Identification and characterization of human ZPBP-like gene in silico. International journal of molecular medicine 58 12883658
2013 Sex- and age-dependent DNA methylation at the 17q12-q21 locus associated with childhood asthma. Human genetics 56 23546690
2017 A meta-analysis of genome-wide association studies of asthma in Puerto Ricans. The European respiratory journal 48 28461288
2016 Optimizing a Male Reproductive Aging Mouse Model by D-Galactose Injection. International journal of molecular sciences 48 26771610
2017 Role of DNA methylation in expression control of the IKZF3-GSDMA region in human epithelial cells. PloS one 36 28241063
2015 Functional variants of 17q12-21 are associated with allergic asthma but not allergic rhinitis. The Journal of allergy and clinical immunology 36 26483175
2011 Association of genetic variants in chromosome 17q21 and adult-onset asthma in a Chinese Han population. BMC medical genetics 34 21985515
2017 Identification of the functional variant driving ORMDL3 and GSDMB expression in human chromosome 17q12-21 in primary biliary cholangitis. Scientific reports 29 28588209
2016 Identification of a new locus at 16q12 associated with time to asthma onset. The Journal of allergy and clinical immunology 28 27130862
2017 Zona pellucida-binding protein 2 (ZPBP2) and several proteins containing BX7B motifs in human sperm may have hyaluronic acid binding or recognition properties. Molecular human reproduction 20 29126140
2020 Genome-wide search for genes affecting the age at diagnosis of type 1 diabetes. Journal of internal medicine 19 33179336
2015 Genetic Determinants of Enterovirus Infections: Polymorphisms in Type 1 Diabetes and Innate Immune Genes in the MIDIA Study. Viral immunology 18 26485223
2018 X chromosome dosage and presence of SRY shape sex-specific differences in DNA methylation at an autosomal region in human cells. Biology of sex differences 17 29463315
2014 Genome-wide association studies (GWAS) and their importance in asthma. Allergologia et immunopathologia 17 25433770
2015 Local genotype influences DNA methylation at two asthma-associated regions, 5q31 and 17q21, in a founder effect population. Journal of medical genetics 16 26671913
2013 Genetic variants on 17q21 are associated with ankylosing spondylitis susceptibility and severity in a Chinese Han population. Scandinavian journal of rheumatology 16 24219690
2021 The Germ Cell-Specific Markers ZPBP2 and PGK2 in Testicular Biopsies Can Predict the Presence as well as the Quality of Sperm in Non-obstructive Azoospermia Patients. Reproductive sciences (Thousand Oaks, Calif.) 15 33507524
2022 Testis-specific serine protease PRSS54 regulates acrosomal granule localization and sperm head morphogenesis in mice†. Biology of reproduction 14 35863763
2020 Long non-coding RNAs lnc-ANGPTL1-3:3 and lnc-GJA10-12:1 present as regulators of sentinel lymph node metastasis in breast cancer. Oncology letters 10 32952657
2016 Polymorphisms and haplotypes of the chromosome locus 17q12-17q21.1 contribute to adult asthma susceptibility in Slovenian patients. Human immunology 10 27163155
2022 17q12-21 risk-variants influence cord blood immune regulation and multitrigger-wheeze. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology 9 34919286
2023 Association of Asthma Risk Alleles With Acute Respiratory Tract Infections and Wheezing Illnesses in Young Children. The Journal of infectious diseases 8 36967681
2021 Association of Gasdermin B Gene GSDMB Polymorphisms with Risk of Allergic Diseases. Biochemical genetics 8 33963941
2017 Association of novel polymorphisms in TMEM39A gene with systemic lupus erythematosus in a Chinese Han population. BMC medical genetics 7 28427360
2024 Sequence variants influencing the regulation of serum IgG subclass levels. Nature communications 6 39277589
2020 Treatment of Allergic Asthma with Fenretinide Formulation (LAU-7b) Downregulates ORMDL Sphingolipid Biosynthesis Regulator 3 (Ormdl3) Expression and Normalizes Ceramide Imbalance. The Journal of pharmacology and experimental therapeutics 6 32273303
2018 Loss of the zona pellucida-binding protein 2 (Zpbp2) gene in mice impacts airway hypersensitivity and lung lipid metabolism in a sex-dependent fashion. Mammalian genome : official journal of the International Mammalian Genome Society 6 29536159
2011 Hyperuricemia cosegregating with osteogenesis imperfecta is associated with a mutation in GPATCH8. Human genetics 6 21594610
2019 Regulatory interaction between the ZPBP2-ORMDL3/Zpbp2-Ormdl3 region and the circadian clock. PloS one 5 31560728
2016 Lymphocyte Activation Dynamics Is Shaped by Hereditary Components at Chromosome Region 17q12-q21. PloS one 4 27835674
2025 Coordinated Transcriptomic and Epigenetic Approach Reveals Molecular Features Underlying Natural Mating Ability in Captive Male Giant Pandas. Ecology and evolution 1 41089893
2010 Molecular cloning of pig ZPBP2 and mRNA expression of ZPBP1 and ZPBP2 in reproductive tracts of boars. Animal reproduction science 1 20846800

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