Affinage

WDR37

WD repeat-containing protein 37 · UniProt Q9Y2I8

Length
494 aa
Mass
54.7 kDa
Annotated
2026-06-11
10 papers in source corpus 5 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WDR37 is a cytoplasmic WD40 repeat protein that functions as a stable binding partner of the PACS proteins PACS1 and PACS2, governing ER calcium homeostasis and lymphocyte quiescence (PMID:33630350, PMID:34642815). It homodimerizes and binds PACS1 and PACS2 strongly, with the interaction mediated by a conserved interface within the PACS1 furin-binding region that stabilizes both proteins and is required for their reciprocal expression (PMID:34642815, PMID:41279321). The PACS1–WDR37 complex is required for normal ER Ca2+ handling: loss of either protein produces peripheral lymphopenia with blunted antigen-receptor-triggered Ca2+ release from the ER, diminished IP3 receptor expression, and elevated ER and oxidative stress (PMID:33630350). Disease-associated WDR37 variants act through distinct molecular failures — abolishing PACS binding while sparing dimerization, reducing protein stability, or impairing function in vivo — and in vivo rescue in Drosophila and dominant-negative behavior of missense alleles in zebrafish establish their pathogenicity (PMID:31327508, PMID:31327510, PMID:34642815).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2019 High

    Established that WDR37 has an essential, conserved organismal function and that human disease variants disrupt it, moving WDR37 from a candidate gene to a functionally validated one.

    Evidence Drosophila null allele with human WT vs. mutant cDNA rescue across seizure, climbing, and grip-strength readouts

    PMID:31327508

    Open questions at the time
    • Molecular activity underlying the phenotypes not defined
    • No biochemical partners identified at this stage
  2. 2019 Medium

    Defined WDR37 as a predominantly cytoplasmic protein and showed missense variants do not grossly alter localization or steady-state levels, indicating pathogenicity arises from a functional rather than trafficking/stability defect for these alleles.

    Evidence Immunocytochemistry and western blot of WT and mutant WDR37 in human cells; zebrafish CRISPR allelic series with RNA-seq

    PMID:31327510

    Open questions at the time
    • Dominant-negative mechanism inferred genetically, not biochemically resolved
    • Cholesterol biosynthesis upregulation not mechanistically linked to WDR37 activity
  3. 2021 High

    Identified the physiological role of the PACS1–WDR37 complex in ER calcium signaling and lymphocyte biology, linking WDR37 to IP3R-dependent Ca2+ release and cellular stress control.

    Evidence Forward genetic screen in mice with independent Pacs1 and Wdr37 knockouts, Ca2+ flux assays, and protein expression analysis

    PMID:33630350

    Open questions at the time
    • Direct molecular link between the complex and IP3R regulation unresolved
    • Whether WDR37 acts catalytically or as a scaffold not determined
  4. 2021 High

    Mapped the protein-interaction logic of WDR37, showing it homodimerizes and binds both PACS1 and PACS2, and that variant pathogenicity can be explained by selective loss of PACS binding or reduced stability.

    Evidence Co-IP, yeast two-hybrid, and immunocytochemistry with structure-function analysis of C-terminal WD40 variants in human cells

    PMID:34642815

    Open questions at the time
    • Functional consequence of PACS-binding loss vs. reduced stability not separated downstream
    • No structural detail of the interaction interface at this stage
  5. 2025 High

    Resolved the structural basis of PACS1–WDR37 assembly, showing PACS1's furin-binding region forms the binding interface and that the complex is mutually stabilizing, reframing how the PACS1-R203W syndrome variant relates to WDR37 dependence.

    Evidence Cryo-EM structure determination with stability assays and targeted WDR37 degradation (preprint)

    PMID:41279321

    Open questions at the time
    • Phospholipid-binding capacity of the FBR cleft inferred from C2-domain homology, not functionally tested
    • How complex assembly couples to ER Ca2+ regulation not structurally addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular activity of WDR37 itself — how the PACS1–WDR37 complex mechanistically controls IP3R expression and ER Ca2+ release — remains undefined.
  • No catalytic or direct effector activity established for WDR37
  • Connection between the structural interface and the calcium phenotype not bridged

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Localization
GO:0005783 endoplasmic reticulum 1 GO:0005829 cytosol 1
Partners
PACS1PACS2WDR37
Complex memberships
PACS1-WDR37 complex

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 Drosophila null allele of the WDR37 ortholog (CG12333/wdr37) causes bang sensitivity (seizure phenotype), climbing defects, and grip strength defects; these phenotypes are rescued by human reference WDR37 cDNA but not by two disease-associated variants, demonstrating that these variants severely impair WDR37 protein function in vivo. Drosophila null allele generation (GAL4 replacement), UAS-cDNA rescue experiments with human wild-type and mutant WDR37 American journal of human genetics High 31327508
2019 Wild-type WDR37 protein is localized predominantly in the cytoplasm; disease-associated missense mutant proteins show similar subcellular localization and similar protein levels compared to wild-type. Immunocytochemistry and western blot in human cells expressing WT and mutant WDR37 American journal of human genetics Medium 31327510
2019 Zebrafish heterozygous for missense variants (including p.Ser129Cys, replicating a human variant) show poor growth and larval lethality, whereas heterozygous frameshift alleles survive to adulthood, indicating a dominant-negative mechanism for the missense variants. RNA-seq of embryos with a missense variant detected significant upregulation of cholesterol biosynthesis pathways. CRISPR-Cas9 genome editing in zebrafish generating missense and frameshift alleles; RNA-seq transcriptomic analysis American journal of human genetics Medium 31327510
2021 Pacs1 and Wdr37 form a complex that is required for normal ER calcium handling in lymphocytes. Deletion of Pacs1 or Wdr37 causes peripheral lymphopenia linked to blunted Ca2+ release from the ER after antigen receptor stimulation, and Pacs1-deficient cells show diminished inositol triphosphate receptor expression together with increased ER and oxidative stress. Forward genetic screening in mice; genetic deletion of Pacs1 or Wdr37; Ca2+ flux measurements; protein expression analysis The EMBO journal High 33630350
2021 WDR37 forms homodimers and strongly binds PACS1 and PACS2; these interactions were confirmed by co-immunoprecipitation, yeast two-hybrid assays, and immunocytochemical colocalization in human cells. A novel disease-associated variant p.(Asp220Gly), located within the second WD40 motif, loses the ability to bind PACS1 and PACS2, while retaining the ability to dimerize with wild-type WDR37. Co-immunoprecipitation, yeast two-hybrid assay, immunocytochemistry; functional variant analysis Human genetics High 34642815
2021 Novel WDR37 disease-associated variants in the C-terminal region (p.Asp220Gly, p.Asp260Asn, p.Pro257His) show normal cellular localization but reduced protein expression levels compared to wild-type WDR37. Immunocytochemistry and western blot in human cells expressing mutant WDR37 Human genetics Medium 34642815
2025 Cryo-EM structure of the Pacs1-Wdr37 complex reveals that Pacs1 binds Wdr37 through a conserved interface within its furin-binding region (FBR). This interaction stabilizes Wdr37 and is critical for the expression of both proteins. The pathogenic Pacs1-R203W mutation (which causes neurodevelopmental syndrome) lies on a solvent-exposed surface of the FBR and does not disrupt complex formation; Pacs1-R203W remains dependent on Wdr37 for stability. Structural homology of the FBR to synaptotagmin C2 domains reveals a potential ability of Pacs1 to bind negatively charged phospholipids through a positively charged cleft. Cryo-electron microscopy structure determination; biochemical stability assays; targeted proteolytic degradation of Wdr37 to reduce Pacs1-R203W levels bioRxivpreprint High 41279321

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia. American journal of human genetics 38 31327508
2019 De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome. American journal of human genetics 30 31327510
2021 Calcium flux control by Pacs1-Wdr37 promotes lymphocyte quiescence and lymphoproliferative diseases. The EMBO journal 26 33630350
2021 WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins. Human genetics 12 34642815
2020 Coloboma may be a shared feature in a spectrum of disorders caused by mutations in the WDR37-PACS1-PACS2 axis. American journal of medical genetics. Part A 11 33369122
2020 Expanding the phenotypic spectrum consequent upon de novo WDR37 missense variants. Clinical genetics 9 32530092
2023 Splicing variant of WDR37 in a case of Neurooculocardiogenitourinary syndrome. Brain & development 2 38044197
2022 First Report of Mexican Patients with PACS1-Related Neurodevelopmental Disorder and Review of the PACS1-, PACS2-, and WDR37-Related Ophthalmological Manifestations. Molecular syndromology 2 37064331
2025 AI-Based Facial Phenotyping Supports a Shared Molecular Axis in PACS1-, PACS2-, and WDR37-Related Syndromes. International journal of molecular sciences 1 40869285
2025 The Structural Basis for Pacs1-Wdr37 Complex Assembly and Stability. bioRxiv : the preprint server for biology 0 41279321

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