Affinage

WRAP73

WD repeat-containing protein WRAP73 · UniProt Q9P2S5

Length
460 aa
Mass
51.6 kDa
Annotated
2026-06-11
15 papers in source corpus 8 papers cited in narrative 8 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

WRAP73 (WDR8) is a conserved WD40-repeat protein that organizes centrosome and spindle architecture by acting as a scaffold at centriolar and spindle pole structures (PMID:26675238, PMID:28098238). In human cells it localizes constitutively to centriolar satellites and the proximal end of the mother centriole, where it associates with the satellite proteins SSX2IP and PCM1 and with the proximal-end component CEP135; CEP135 recruits WRAP73 to centrioles, and together WRAP73 and CEP135 drive ciliary vesicle docking and displacement of the CP110-Cep97 inhibitory complex to initiate ciliogenesis (PMID:26675238). WRAP73 acts upstream of SSX2IP at the mitotic centrosome, where its depletion shortens and misorients spindle microtubules, defining a conserved SSX2IP-WRAP73-CEP135 module that controls spindle length and orientation (PMID:26545777, PMID:35406752). The conserved mechanism is illuminated by the fission yeast ortholog, where a Msd1-Wdr8-kinesin-14 (Pkl1) complex anchors spindle microtubule minus ends at spindle pole bodies and balances outward kinesin-5 (Cut7) force to maintain spindle bipolarity (PMID:25987607), and by the medaka ortholog, where Wdr8 is a maternally essential centrosome-assembly factor whose WD40 domains bind SSX2IP to safeguard zygotic genome stability (PMID:28098238). A homozygous WRAP73 missense mutation (p.Pro383Leu) that destabilizes the protein and disrupts partner binding causes isolated Microspherophakia, with eye and lens defects in zebrafish rescued by wild-type but not mutant human WRAP73 (PMID:33693649).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2001 Low

    Established WDR8 as a distinct WD-repeat protein and raised the first functional hint by linking its expression to a developmental transition.

    Evidence Differential display cloning, Northern blot, and expression profiling in a chondrogenic cell line

    PMID:11401440

    Open questions at the time
    • Identification and expression profiling only, no mechanistic or interaction data
    • No subcellular localization or molecular partners defined
    • Proposed ossification role untested functionally
  2. 2013 Medium

    First mitotic function: showed an Aspergillus WDR8 ortholog acts in a mutual stabilization/targeting relationship with TINA to anchor mitotic microtubules at spindle pole bodies.

    Evidence Affinity purification, deletion mutant analysis, and 4D confocal live imaging in Aspergillus nidulans

    PMID:24152731

    Open questions at the time
    • Fungal ortholog; human TINA equivalent not addressed
    • Single lab
    • Molecular basis of microtubule anchoring not resolved
  3. 2015 High

    Defined a conserved force-balancing mechanism: the Msd1-Wdr8-Pkl1 complex tethers a minus-end-directed kinesin at the SPB to counter kinesin-5 outward force and maintain spindle bipolarity.

    Evidence Genetic deletion and epistasis (double-mutant suppression), live fluorescence microscopy, and co-immunoprecipitation in fission yeast

    PMID:25987607

    Open questions at the time
    • Whether the human complex engages an analogous kinesin force balance untested
    • Structural basis of Pkl1 tethering by Msd1-Wdr8 unresolved
  4. 2015 High

    Placed human WDR8 at the proximal mother centriole and centriolar satellites and assigned it an SSX2IP/CEP135-linked role initiating ciliogenesis through ciliary vesicle docking and CP110-Cep97 displacement.

    Evidence Reciprocal Co-IP, RNAi depletion with ciliogenesis readouts, and super-resolution immunofluorescence in human cells

    PMID:26675238

    Open questions at the time
    • How WDR8/CEP135 mechanistically promotes vesicle docking is undefined
    • No structure of the SSX2IP-WDR8-CEP135 complex
  5. 2015 Medium

    Ordered the human complex hierarchy, showing WDR8 acts upstream of SSX2IP recruitment to the mitotic centrosome and controls spindle length and orientation.

    Evidence Mass spectrometry interactor identification, RNAi knockdown, super-resolution microscopy, and Co-IP in human cells

    PMID:26545777

    Open questions at the time
    • Single lab
    • Direct versus indirect WDR8-SSX2IP binding not separated from satellite context
    • Force-generating mechanism for spindle length control not shown
  6. 2017 High

    Demonstrated an essential physiological role: maternal Wdr8 is required for embryonic centrosome assembly, with its WD40 domains binding SSX2IP to preserve zygotic genome stability.

    Evidence CRISPR-Cas9 maternal/zygotic knockout, in vivo reconstitution, Co-IP, and live imaging in medaka

    PMID:28098238

    Open questions at the time
    • Relevance to mammalian embryonic centrosome assembly not tested
    • How Wdr8 templates centrosome structure mechanistically unresolved
  7. 2021 High

    Linked WDR8 to human disease, showing a destabilizing missense mutation that disrupts partner binding causes isolated Microspherophakia with cell-cycle defects in retinal/lens tissue.

    Evidence Homozygosity mapping, exome sequencing, in vitro stability assay, Co-IP, and morpholino/CRISPR knockdown with human-WRAP73 rescue in zebrafish

    PMID:33693649

    Open questions at the time
    • Which specific partner interactions drive the lens phenotype not pinpointed
    • Tissue-specific basis for an isolated ocular phenotype unexplained
  8. 2022 Medium

    Refined the somatic-cell picture, showing the SSX2IP-WDR8-CEP135 complex assembles before centrosome formation but WDR8 loss is compensated in established somatic lines, unlike CEP135.

    Evidence Stable CRISPR knockout and quantitative centrosome phenotype analysis in human cell lines

    PMID:35406752

    Open questions at the time
    • Nature of the compensatory mechanism for WDR8 loss unknown
    • Why WDR8 is dispensable somatically but essential maternally unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the WDR8-SSX2IP-CEP135 complex is structurally organized and mechanistically couples centriolar anchoring to spindle force balance, ciliary vesicle docking, and tissue-specific developmental outcomes remains open.
  • No high-resolution structure of the complex
  • Direct biochemical demonstration of microtubule minus-end anchoring by human WDR8 absent
  • Mechanistic link between molecular defect and isolated ocular disease undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005815 microtubule organizing center 2
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
CEP135PCM1PKL1SSX2IPTINA
Complex memberships
Msd1-Wdr8-Pkl1 complex (fission yeast)SSX2IP-WDR8-CEP135 complex

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 Fission yeast Wdr8 forms a ternary complex with Msd1 and the minus end-directed kinesin-14 Pkl1 at spindle pole bodies (SPBs). Msd1 and Wdr8 are delivered to mitotic SPBs by Pkl1, where Pkl1 is tethered through Msd1-Wdr8. The spindle-anchoring defect imposed by msd1/wdr8/pkl1 deletions is suppressed by a mutation in plus end-directed Cut7/kinesin-5, indicating that the Msd1-Wdr8-Pkl1 complex balances Cut7-mediated outward force at the SPB to ensure spindle bipolarity. Pkl1 motor activity was not required for its anchoring role once targeted to the SPB. Genetic deletion analysis, genetic epistasis (double mutant suppression), live fluorescence microscopy, co-immunoprecipitation The Journal of cell biology High 25987607
2015 Human WDR8 (WRAP73) localizes to centriolar satellites and to the proximal end of the mother centriole. WDR8 interacts with the satellite proteins SSX2IP and PCM1, and with the centriolar proximal end component Cep135. Cep135 is required for WDR8 recruitment to centrioles. WDR8 and Cep135 are both indispensable for ciliary vesicle docking to the mother centriole and for displacement of the ciliary inhibitory complex CP110-Cep97, establishing a role for WDR8 in the initial steps of ciliogenesis. Co-immunoprecipitation, RNAi depletion with ciliogenesis phenotypic readout, immunofluorescence localization, super-resolution microscopy Journal of cell science High 26675238
2013 In Aspergillus nidulans, An-WDR8 (ortholog of WRAP73/WDR8) co-purifies with TINA (a NIMA-interacting protein) and is required for TINA stability and mitotic targeting; reciprocally, TINA is required for mitotic SPB targeting of An-WDR8. Together, TINA and An-WDR8 are required for anchoring mitotic microtubules to SPBs and for successful mitosis. Affinity purification, 4D spinning disk confocal microscopy, deletion mutant analysis, GFP-tagging localization studies Molecular biology of the cell Medium 24152731
2015 Human Wdr8 constitutively localizes to the centrosome, enriched at the proximal end of the mother centriole. Wdr8 forms a complex with hMsd1/SSX2IP identified by mass spectrometry. Knockdown of Wdr8 results in shortened and misoriented spindle microtubules, and reduces recruitment of hMsd1/SSX2IP to the mitotic centrosome (but depletion of hMsd1/SSX2IP does not affect Wdr8 centrosomal localization), indicating that Wdr8 acts upstream of hMsd1/SSX2IP in a conserved complex controlling spindle length and orientation. Mass spectrometry (interactor identification), RNAi knockdown, super-resolution microscopy, immunofluorescence, co-immunoprecipitation Biochemical and biophysical research communications Medium 26545777
2017 Wdr8 is a maternally essential protein required for centrosome assembly during embryonic mitoses in medaka fish. CRISPR-Cas9 knockout of maternal/zygotic Wdr8 causes defects in centrosome structure leading to asymmetric division, multipolar spindles, and chromosome alignment errors. Via its WD40 domains, Wdr8 interacts with the centriolar satellite protein SSX2IP. In vivo reconstitution of the Wdr8-SSX2IP complex reveals an essential link between maternal centrosome proteins and zygotic genome stability. CRISPR-Cas9 knockout, in vivo reconstitution, co-immunoprecipitation, live fluorescence microscopy Nature communications High 28098238
2021 A homozygous missense mutation in WDR8 (p.Pro383Leu) causes isolated Microspherophakia in humans. In vitro experiments showed the mutation renders the protein unstable. Co-immunoprecipitation from HeLa cells indicated the mutation interferes with WDR8 interaction with its binding partners. In zebrafish, morpholino knockdown and CRISPR/Cas9 knockout of wdr8 resulted in decreased eye and lens size and defective cell cycle progression in retinal cells; these defects were rescued by wild-type human WDR8 but not by the p.Pro383Leu mutant. Homozygosity mapping, whole-exome sequencing, in vitro protein stability assay, co-immunoprecipitation, morpholino knockdown, CRISPR/Cas9 knockout, rescue experiments in zebrafish Human molecular genetics High 33693649
2022 In human somatic cells, SSX2IP, WDR8, and CEP135 form a complex that is assembled before centrosome assembly in vertebrate oocytes and functionally interacts in somatic cells. Stable knockout of WDR8 in human cells is compensated for during mitosis; WDR8 loss does not cause severe mitotic phenotypes in established somatic cell lines, unlike CEP135 knockout which compromises PCM recruitment and causes premature centrosome splitting. Stable CRISPR knockout in human cell lines, immunofluorescence, centrosome phenotype analysis Cells Medium 35406752
2001 WDR8 encodes a novel WD-repeat protein of 460 amino acids (human) that is expressed in almost all tissues including bone and cartilage. It represents a novel subfamily of WD-repeat proteins distinctly different from other family members. Wdr8 expression in cartilage is regulated during the transition from hypertrophic to mineralizing stages in a chondrogenic cell line (ATDC5), suggesting a role in ossification. Differential display cloning, Northern blot, expression profiling in cell lines Genomics Low 11401440

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Association of dietary folate and vitamin B-12 intake with genome-wide DNA methylation in blood: a large-scale epigenome-wide association analysis in 5841 individuals. The American journal of clinical nutrition 56 31165884
2015 The Msd1-Wdr8-Pkl1 complex anchors microtubule minus ends to fission yeast spindle pole bodies. The Journal of cell biology 47 25987607
2015 WDR8 is a centriolar satellite and centriole-associated protein that promotes ciliary vesicle docking during ciliogenesis. Journal of cell science 32 26675238
2013 Regulation of mitosis by the NIMA kinase involves TINA and its newly discovered partner, An-WDR8, at spindle pole bodies. Molecular biology of the cell 22 24152731
2024 Blood DNA methylation signature of diet quality and association with cardiometabolic traits. European journal of preventive cardiology 18 37793095
2001 Isolation, characterization, and mapping of the mouse and human WDR8 genes, members of a novel WD-repeat gene family. Genomics 18 11401440
2021 An anchoring complex recruits katanin for microtubule severing at the plant cortical nucleation sites. Nature communications 17 34140499
2015 The conserved Wdr8-hMsd1/SSX2IP complex localises to the centrosome and ensures proper spindle length and orientation. Biochemical and biophysical research communications 17 26545777
2023 Genome-Wide Methylation Profiling in 229 Patients With Crohn's Disease Requiring Intestinal Resection: Epigenetic Analysis of the Trial of Prevention of Post-operative Crohn's Disease (TOPPIC). Cellular and molecular gastroenterology and hepatology 13 37331566
2022 Identification of combined biomarkers for predicting the risk of osteoporosis using machine learning. Aging 9 35580864
2017 Expression of the novel maternal centrosome assembly factor Wdr8 is required for vertebrate embryonic mitoses. Nature communications 9 28098238
2024 Plant microtubule nucleating apparatus and its potential signaling pathway. Current opinion in plant biology 7 39232346
2022 Mitotic Maturation Compensates for Premature Centrosome Splitting and PCM Loss in Human cep135 Knockout Cells. Cells 7 35406752
2008 A genome-wide linkage scan for low spinal bone mineral density in a single extended family confirms linkage to 1p36.3. European journal of human genetics : EJHG 5 18285824
2021 Exome sequencing and functional studies in zebrafish identify WDR8 as the causative gene for isolated Microspherophakia in Indian families. Human molecular genetics 2 33693649

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