Affinage

PACRG

Parkin coregulated gene protein · UniProt Q96M98

Length
296 aa
Mass
33.3 kDa
Annotated
2026-06-10
35 papers in source corpus 15 papers cited in narrative 15 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

PACRG is an evolutionarily conserved axonemal protein required for the structural integrity and motility of cilia and flagella (PMID:16278296, PMID:31116684). Together with FAP20, it forms the inner junction bridge linking the A- and B-tubules along all nine ciliary doublet microtubules, and loss of either protein causes severe motility defects, reduced microtubule sliding velocities, and defective assembly of inner-arm dynein and beak-MIP structures (PMID:31116684). PACRG binds microtubules and α/β-tubulin heterodimers directly with high affinity through a conserved sequence region (PMID:18387367), and structural and single-molecule analyses indicate it simultaneously engages microtubules and recruits free tubulin to catalyze inner-junction formation (PMID:33529594); with FAP20 it stabilizes B-tubule dynamics by suppressing depolymerization and reducing curvature fluctuations [PMID:bio_10.1101_2025.03.12.642377]. Beyond its structural role, PACRG participates in a doublet-anchored signaling pathway that interacts with radial spokes to regulate dynein-driven sliding (PMID:27770595). In elongating spermatids, PACRG forms a complex with MEIG1 in the manchette to transport cargo such as SPAG16L for sperm flagellum assembly; PACRG recruits MEIG1 to the manchette, and MEIG1 reciprocally stabilizes the otherwise proteasomally degraded PACRG (PMID:25715396, PMID:26726850). This complex is scaffolded by DNALI1, which is required for its manchette localization (PMID:37083624), and PACRG is further stabilized by UCHL3-mediated deubiquitination (PMID:41058558). Outside the cilium, PACRG promotes TNF-induced NF-κB activation by stabilizing the LUBAC complex; it is recruited to the activated TNF receptor complex and can functionally substitute for SHARPIN to restore HOIP-dependent linear ubiquitylation and protect cells from TNF-induced apoptosis (PMID:32019898).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2005 High

    Established PACRG as an axonemal protein required for the structural stability of outer doublet microtubules, answering whether it has a role in ciliary/flagellar architecture.

    Evidence RNAi knockdown of both PACRG homologues, GFP localization, and TEM in T. brucei

    PMID:16278296

    Open questions at the time
    • Did not resolve the molecular position of PACRG within the doublet
    • No direct biochemical binding partner identified
  2. 2007 Medium

    Refined PACRG's localization to the region between A- and B-tubules and showed it is buried within the microtubule wall, pointing to an inter-tubule structural function.

    Evidence Immuno-EM and Sarkosyl extraction in Chlamydomonas

    PMID:17654607

    Open questions at the time
    • Structural inference not confirmed by direct binding assay at this stage
    • Did not define partner proteins at the junction
  3. 2008 Medium

    Demonstrated that PACRG binds microtubules and tubulin dimers directly and with high affinity, providing the biochemical basis for its structural role.

    Evidence In vitro co-sedimentation and microscopy of PACRG-tubulin complexes

    PMID:18387367

    Open questions at the time
    • In vitro bundling/aggregation behavior may not reflect axonemal context
    • Single lab, single study
  4. 2015 High

    Identified the MEIG1/PACRG manchette complex and ordered it genetically, answering how PACRG contributes to sperm flagellum assembly via cargo transport.

    Evidence Yeast two-hybrid, knockout mouse colocalization, proteasome inhibition

    PMID:25715396

    Open questions at the time
    • Mechanism of cargo loading/release not defined
    • Transport machinery linking complex to motors unresolved
  5. 2016 High

    Mapped the MEIG1 hydrophobic patch required for PACRG binding and stabilization, defining the molecular interface of the complex.

    Evidence Systematic mutagenesis of MEIG1 and bacterial co-expression binding/stability assays

    PMID:26726850

    Open questions at the time
    • PACRG-side interface not defined here
    • Structural basis of stabilization not resolved
  6. 2016 Medium

    Placed PACRG within a doublet-anchored signaling pathway regulating dynein-driven sliding through interaction with radial spokes.

    Evidence In vitro microtubule sliding assays and biochemical pulldowns

    PMID:27770595

    Open questions at the time
    • Direct radial-spoke binding partner not identified
    • Single lab
  7. 2016 Medium

    Extended PACRG function to nonmotile cilia and signaling/longevity pathways in C. elegans, indicating roles beyond motile axoneme structure.

    Evidence C. elegans loss-of-function genetics, behavioral assays, daf-16/FOXO epistasis

    PMID:27193298

    Open questions at the time
    • Molecular link between PACRG and G-protein/insulin signaling not defined
    • Conservation of this role in mammals unknown
  8. 2019 High

    Resolved that PACRG and FAP20 jointly form the inner-junction bridge and are required for sliding and dynein/MIP assembly, with add-back reconstitution restoring function.

    Evidence Cryo-ET, microtubule sliding assays, Chlamydomonas mutants, purified-protein add-back

    PMID:31116684

    Open questions at the time
    • Add-back restored sliding but not beating, leaving the beating defect unexplained
    • Stoichiometry with FAP20 not fully defined
  9. 2020 High

    Revealed a noncanonical PACRG function in TNF/NF-κB signaling, showing it stabilizes LUBAC and can functionally replace SHARPIN.

    Evidence Reciprocal co-IP, TNF receptor complex pulldown, NF-κB reporters, complementation in SHARPIN-KO cells, linear ubiquitylation assays

    PMID:32019898

    Open questions at the time
    • Structural basis of PACRG-LUBAC interaction unknown
    • Physiological context where PACRG substitutes for SHARPIN in vivo not established
  10. 2021 High

    Determined the PACRG fold and PACRG-MEIG1 interface and proposed a tubulin-recruitment mechanism for inner-junction catalysis.

    Evidence X-ray crystallography of PACRG-MEIG1, single-molecule fluorescence, structural modeling

    PMID:33529594

    Open questions at the time
    • Catalytic mechanism of junction assembly inferred, not directly observed
    • Functional role of PACRG-like paralog not defined
  11. 2023 High

    Identified DNALI1 as the upstream scaffold required for manchette assembly of the MEIG1/PACRG complex, refining the spermiogenesis pathway.

    Evidence Co-IP/pulldown and conditional knockout mice with immunofluorescence

    PMID:37083624

    Open questions at the time
    • How DNALI1 anchors the complex to the manchette structurally is unresolved
    • Cargo-transport mechanism downstream remains undefined
  12. 2025 Medium

    Showed UCHL3 deubiquitinates and stabilizes PACRG, with DNAH10 bridging the interaction, defining how PACRG protein levels are maintained during spermiogenesis.

    Evidence Co-IP, deubiquitination assays, localization in Dnah10-deficient mice

    PMID:41058558

    Open questions at the time
    • Single lab, single study
    • Ubiquitin sites on PACRG and the ligase responsible not identified
  13. 2025 High

    Demonstrated by cell-free reconstitution that PACRG and FAP20 together stabilize B-tubule dynamics and rigidity, directly linking the inner junction to microtubule mechanical behavior.

    Evidence Cell-free reconstitution, TIRF microscopy, cryo-ET (preprint)

    PMID:bio_10.1101_2025.03.12.642377

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Relationship between in vitro rigidity changes and in vivo beating defects not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PACRG's distinct roles in axonemal structure, spermatid cargo transport, and LUBAC-dependent NF-κB signaling are coordinated or regulated within a single cell remains unresolved.
  • No unifying regulatory mechanism connecting ciliary and immune-signaling roles
  • Determinants of PACRG localization/partner choice unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 4 GO:0005198 structural molecule activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005929 cilium 4 GO:0005856 cytoskeleton 3 GO:0005829 cytosol 2 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-1474165 Reproduction 2 R-HSA-162582 Signal Transduction 2 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-168256 Immune System 1
Partners
DNAH10DNALI1FAP20HOIPMEIG1SHARPINSPAG16LUCHL3
Complex memberships
LUBACMEIG1/PACRG complexinner junction (with FAP20)

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 PACRG localizes along the full length of the axoneme in Trypanosoma brucei (GFP fusion); RNAi knockdown of both T. brucei PACRG homologues simultaneously caused flagellar paralysis, slow growth, defective organelle segregation, and structural loss of outer doublet microtubules from the canonical 9+2 formation, establishing PACRG as an axonemal protein required for functional stability of outer doublet microtubules in both motile and sensory cilia/flagella. RNAi knockdown in T. brucei, GFP fusion localization, transmission electron microscopy Journal of cell science High 16278296
2007 Chlamydomonas PACRG localizes to the entire length of the axoneme and basal body; immunoelectron microscopy shows PACRG antigen is densely distributed along outer doublets between the A- and B-tubules of adjacent outer doublets, suggesting a structural role in inter-tubule linkage. Sarkosyl pretreatment required for immunolocalization indicates PACRG is buried within the microtubule wall. Indirect immunofluorescence, immuno-electron microscopy, Sarkosyl extraction Cell motility and the cytoskeleton Medium 17654607
2007 PACRG protein is regulated by the ubiquitin-proteasomal system; PACRG was detected in Lewy bodies and glial cytoplasmic inclusions in Parkinson's disease and Multiple System Atrophy patients, and in astrocytes and locus coeruleus neurons of normal brain. Immunohistochemistry, proteasome inhibition assays Neurobiology of disease Medium 17590346
2008 PACRG directly binds to microtubules and alpha/beta-tubulin heterodimers with high affinity via a highly conserved amino acid sequence region; PACRG bundles microtubules and forms branched aggregates with unpolymerized tubulin dimers in vitro. Co-sedimentation assays, microscopy of PACRG-tubulin complexes in vitro FEBS letters Medium 18387367
2015 MEIG1 and PACRG form a complex in the manchette of elongating spermatids that is essential for transporting cargo (e.g., SPAG16L) to build the sperm flagellum. PACRG recruits MEIG1 to the manchette (MEIG1 fails to localize to the manchette in Pacrg-deficient mice). PACRG is unstable in mammalian cells but is stabilized by MEIG1 or proteasome inhibition. SPAG16L is a downstream cargo of the MEIG1/PACRG complex. Yeast two-hybrid, colocalization by immunofluorescence in wild-type and knockout mice, proteasome inhibition assay Development (Cambridge, England) High 25715396
2016 PACRG and its interactors form part of a signaling pathway anchored to axonemal doublet microtubules that includes the central apparatus, radial spokes, and specific inner dynein arm subforms to control dynein-driven microtubule sliding; PACRG biochemically interacts with radial spokes. In vitro microtubule sliding assay, biochemical pulldown/interaction assay Cytoskeleton (Hoboken, N.J.) Medium 27770595
2016 In C. elegans, PACRG localizes to a small subset of nonmotile cilia and influences gustatory plasticity learning behavior through functional coupling to heterotrimeric G-protein signaling; PACRG also promotes longevity by acting upstream of the FOXO transcription factor DAF-16 and likely upstream of insulin/IGF signaling. C. elegans loss-of-function genetics, behavioral assays (gustatory plasticity), epistasis with daf-16/FOXO pathway, localization imaging Molecular biology of the cell Medium 27193298
2016 MEIG1 adopts a unique fold with a large interaction surface; four residues (W50, K57, F66, Y68) forming a contiguous hydrophobic patch are required for PACRG binding, and these same mutations abolish MEIG1's ability to stabilize PACRG when co-expressed in bacteria. Mutagenesis of 12 conserved MEIG1 residues, co-expression binding/stability assays in bacteria Scientific reports High 26726850
2019 PACRG and FAP20 together form the inner junction bridge between the A- and B-tubules along the length of all nine ciliary doublet microtubules in Chlamydomonas; loss of PACRG and/or FAP20 causes severe motility defects, reduced microtubule sliding velocities, and reduced assembly of inner-arm dynein IDA b and beak-MIP structures. Addition of exogenous PACRG and/or FAP20 to isolated mutant axonemes restores sliding velocities but not ciliary beating. Cryo-electron tomography, in vitro microtubule sliding assay, Chlamydomonas pacrg mutants, add-back reconstitution with purified protein Molecular biology of the cell High 31116684
2020 PACRG promotes TNF-induced NF-κB activation by stabilizing LUBAC (the linear ubiquitin chain assembly complex composed of HOIP, HOIL-1L, and SHARPIN). Upon TNF stimulation, PACRG is recruited to the activated TNF receptor complex and interacts with LUBAC components. In SHARPIN-deficient cells, PACRG functionally replaces SHARPIN, prevents LUBAC destabilization, restores HOIP-dependent linear ubiquitylation, and protects cells from TNF-induced apoptosis. PACRG does not play a role in mitophagy. Co-immunoprecipitation, TNF receptor complex pulldown, NF-κB reporter assays, PACRG-deficient and SHARPIN-deficient cell lines, linear ubiquitylation assay Science signaling High 32019898
2021 Crystal structure of human PACRG in complex with MEIG1 reveals that PACRG adopts a helical repeat fold with a loop that interacts with MEIG1. Using the Chlamydomonas axonemal doublet microtubule structure and single-molecule fluorescence microscopy, PACRG is proposed to bind microtubules while simultaneously recruiting free tubulin to catalyze formation of the inner junction. The homologous PACRG-like protein also mediates dual tubulin interactions but does not bind MEIG1. X-ray crystallography (crystal structure of PACRG–MEIG1 complex), single-molecule fluorescence microscopy, structural modeling with cryo-EM axonemal structure Structure (London, England : 1993) High 33529594
2023 DNALI1 recruits and stabilizes PACRG via direct interaction (co-immunoprecipitation and pull-down); DNALI1 is required for the formation and manchette localization of the MEIG1/PACRG complex. In Dnali1-deficient mice, MEIG1, PACRG, and SPAG16L protein levels are unchanged but their localization within the manchette is lost, placing DNALI1 upstream of MEIG1/PACRG complex assembly at the manchette. Co-immunoprecipitation, pull-down assays, conditional knockout mice, immunofluorescence localization eLife High 37083624
2012 PACRG morpholino knockdown in Xenopus laevis caused left-right axis specification defects (randomized laterality), neural tube closure defects, and gastrulation defects dose-dependently, indicating ciliary and non-ciliary functions. A GFP fusion of PACRG preferentially labeled cilia and also showed perinuclear and cytoplasmic localization. Antisense morpholino knockdown in Xenopus, timelapse videography of leftward flow, scanning electron microscopy, whole-mount in situ hybridization, GFP fusion localization Cilia Medium 23351225
2025 UCHL3 (ubiquitin carboxyl-terminal hydrolase L3) binds to PACRG and stabilizes it via deubiquitination; DNAH10 acts as a bridging protein that enhances the UCHL3-PACRG interaction to facilitate their involvement in manchette function and intra-manchette transport during spermiogenesis. Co-immunoprecipitation, deubiquitination assay, localization studies in Dnah10-deficient mice Development (Cambridge, England) Medium 41058558
2025 In a cell-free reconstitution system, PACRG and FAP20 together (but not individually) stabilize B-tubule dynamics by decreasing depolymerization velocity and increasing rescue frequency; cryo-electron tomography of in vitro reconstituted microtubule doublets with PACRG and FAP20 shows reduced B-tubule curvature fluctuations, promoting a more rigid and aligned conformation. The two proteins localize to B-tubules in distinct high-density patches. Cell-free reconstitution assay, TIRF microscopy, cryo-electron tomography bioRxivpreprint High bio_10.1101_2025.03.12.642377

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Susceptibility to leprosy is associated with PARK2 and PACRG. Nature 353 14737177
2005 The Parkin co-regulated gene product, PACRG, is an evolutionarily conserved axonemal protein that functions in outer-doublet microtubule morphogenesis. Journal of cell science 83 16278296
2006 PARK2/PACRG polymorphisms and susceptibility to typhoid and paratyphoid fever. Clinical and experimental immunology 69 16734611
2018 Bifunctional Enzyme SpoT Is Involved in Biofilm Formation of Helicobacter pylori with Multidrug Resistance by Upregulating Efflux Pump Hp1174 (gluP). Antimicrobial agents and chemotherapy 64 30181372
2015 A MEIG1/PACRG complex in the manchette is essential for building the sperm flagella. Development (Cambridge, England) 50 25715396
2004 It's a double knock-out! The quaking mouse is a spontaneous deletion of parkin and parkin co-regulated gene (PACRG). Movement disorders : official journal of the Movement Disorder Society 48 14743368
2019 PACRG and FAP20 form the inner junction of axonemal doublet microtubules and regulate ciliary motility. Molecular biology of the cell 43 31116684
2007 Deletion of the parkin and PACRG gene promoter in early-onset parkinsonism. Human mutation 36 17068781
2007 Axonemal localization of Chlamydomonas PACRG, a homologue of the human Parkin-coregulated gene product. Cell motility and the cytoskeleton 35 17654607
2007 Parkin Co-Regulated Gene (PACRG) is regulated by the ubiquitin-proteasomal system and is present in the pathological features of Parkinsonian diseases. Neurobiology of disease 33 17590346
2022 Distinction between Enterococcus faecium and Enterococcus lactis by a gluP PCR-Based Assay for Accurate Identification and Diagnostics. Microbiology spectrum 27 36453910
2008 Parkin-co-regulated gene (PACRG) product interacts with tubulin and microtubules. FEBS letters 27 18387367
2004 Expression of a novel gene, gluP, is essential for normal Bacillus subtilis cell division and contributes to glucose export. BMC microbiology 26 15050034
2017 Glucose uptake in Azotobacter vinelandii occurs through a GluP transporter that is under the control of the CbrA/CbrB and Hfq-Crc systems. Scientific reports 24 28404995
2012 PARK2 and PACRG are commonly downregulated in clear-cell renal cell carcinoma and are associated with aggressive disease and poor clinical outcome. Genes, chromosomes & cancer 24 23125027
2013 Mapping of PARK2 and PACRG overlapping regulatory region reveals LD structure and functional variants in association with leprosy in unrelated indian population groups. PLoS genetics 22 23861666
2021 Crystal structure of human PACRG in complex with MEIG1 reveals roles in axoneme formation and tubulin binding. Structure (London, England : 1993) 20 33529594
2016 PACRG, a protein linked to ciliary motility, mediates cellular signaling. Molecular biology of the cell 18 27193298
2018 Generation and characterisation of a parkin-Pacrg knockout mouse line and a Pacrg knockout mouse line. Scientific reports 16 29760428
2020 The parkin-coregulated gene product PACRG promotes TNF signaling by stabilizing LUBAC. Science signaling 15 32019898
2016 Dissecting the structural basis of MEIG1 interaction with PACRG. Scientific reports 14 26726850
2023 DNALI1 interacts with the MEIG1/PACRG complex within the manchette and is required for proper sperm flagellum assembly in mice. eLife 13 37083624
2012 Ciliary and non-ciliary expression and function of PACRG during vertebrate development. Cilia 12 23351225
2005 Genetic analysis of parkin co-regulated gene (PACRG) in patients with early-onset parkinsonism. Neuroscience letters 12 15925106
2020 Associations of PRKN-PACRG SNPs and G × G and G × E interactions with the risk of hyperlipidaemia. Scientific reports 6 32747620
2016 Microtubule binding protein PACRG plays a role in regulating specific ciliary dyneins during microtubule sliding. Cytoskeleton (Hoboken, N.J.) 6 27770595
2019 Impact of the Polymorphism of the PACRG and CD80 Genes on the Development of the Different Stages of Tuberculosis Infection. Iranian journal of medical sciences 5 31182890
2011 Leprosy epidemics during history increased protective allele frequency of PARK2/PACRG genes in the population of the Mljet Island, Croatia. European journal of medical genetics 5 21816242
2021 Functional Expression, Purification and Identification of Interaction Partners of PACRG. Molecules (Basel, Switzerland) 4 33923444
2022 Molecular dynamics study reveals key disruptors of MEIG1-PACRG interaction. Proteins 3 36444670
2025 In Silico Discovery of Potential Inhibitors Targeting the MEIG1-PACRG Complex for Male Contraceptive Development. Proteins 0 40265567
2025 DNAH10 interacts with UCHL3-PACRG complex to coordinate sperm head and flagella development during spermiogenesis. Development (Cambridge, England) 0 41058558
2024 In silico discovery of potential inhibitors targeting the MEIG1-PACRG complex for male contraceptive development. bioRxiv : the preprint server for biology 0 39763986
2024 PACRG is Expressed on the Left Side of the Brain Vesicle in the Ascidian Halocynthia Larva. Development & reproduction 0 39845515
2016 [Construction of a GFP-fused mouse PACRG baculovirus recombinant vector and expression of the fusion protein in Sf9 inset cells]. Zhonghua nan ke xue = National journal of andrology 0 28965374

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