Affinage

TUBGCP2

Gamma-tubulin complex component 2 · UniProt Q9BSJ2

Length
902 aa
Mass
102.5 kDa
Annotated
2026-06-10
12 papers in source corpus 10 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TUBGCP2 (GCP2) is a core structural subunit of the gamma-tubulin complex that nucleates microtubules from microtubule organizing centers and is required for spindle assembly and centrosome/spindle pole body (SPB) function (PMID:9384578, PMID:9130700, PMID:9566967). Work on its yeast ortholog Spc97p established that it assembles with gamma-tubulin (Tub4p) and Spc98p (GCP3) into a defined trimeric 6S complex containing one copy each of Spc97p and Spc98p plus gamma-tubulin (PMID:9384578), and that this complex is tethered to the SPB through the N-terminal domain of Spc110p (PMID:9384578, PMID:9130700). The complex is essential for microtubule organization, SPB duplication and separation, and bipolar spindle formation, with loss-of-function alleles producing monopolar/spindle defects and checkpoint activation (PMID:9130700, PMID:11952833). In mammals, human GCP2 is a homolog of Spc97p that colocalizes and co-sediments with gamma-tubulin at the centrosome (PMID:9566967), and it binds gamma-tubulin through a defined surface interface mapped on gamma-tubulin and interacts with GCP3 (PMID:15280226). The N-terminal domain of GCP2 governs competitive incorporation into the large (>2000 kDa) gamma-TuRC (PMID:23886939), and the balance between nuclear and cytoplasmic gamma-tubulin complex activity controls cytoplasmic microtubule stability, nuclear positioning, and cell-cycle progression (PMID:16611238, PMID:16611237). Bi-allelic pathogenic TUBGCP2 variants cause autosomal recessive microcephaly and lissencephaly spectrum disorders, linking gamma-TuRC function to neuronal migration during cortical development (PMID:31630790).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1997 High

    Defined the minimal composition of the gamma-tubulin complex, establishing that the TUBGCP2 ortholog is a stoichiometric structural partner of gamma-tubulin rather than a loosely associated factor.

    Evidence Biochemical purification, sucrose gradient fractionation, and immunoprecipitation of the Tub4p complex in budding yeast

    PMID:9384578

    Open questions at the time
    • Stoichiometry of Tub4p (≥2 copies) not precisely resolved
    • Higher-order ring assembly not addressed in this minimal complex
  2. 1997 High

    Showed how the complex is anchored to the spindle pole body, answering how gamma-tubulin nucleation activity is spatially targeted.

    Evidence Genetic suppression, two-hybrid, and biochemical pulldown mapping Spc97p/Spc98p interaction to the N-terminal domain of Spc110p in yeast

    PMID:9130700 PMID:9384578

    Open questions at the time
    • Whether the human Spc110p equivalent uses the same anchoring mechanism not addressed
  3. 1997 High

    Established the in vivo functional requirement of the TUBGCP2 ortholog for SPB duplication, separation, and spindle formation.

    Evidence Temperature-sensitive spc97 alleles, two-hybrid, co-IP, and high-copy genetic suppression by SPC98/TUB4

    PMID:9130700

    Open questions at the time
    • Molecular basis of how complex loss blocks SPB duplication not defined
  4. 1998 High

    Extended the yeast model to mammals by identifying human GCP2 as a gamma-tubulin complex component at the centrosome.

    Evidence Epitope-tagged gamma-tubulin stable cell lines, co-IP, sucrose gradient cosedimentation, and immunofluorescence colocalization

    PMID:9566967

    Open questions at the time
    • Human complex stoichiometry and ring assembly not resolved
    • Direct GCP2-gamma-tubulin binding interface in human not mapped here
  5. 2002 Medium

    Connected gamma-tubulin complex recruitment to mitotic checkpoint and septation signaling, showing spindle defects feed into cell-cycle control networks.

    Evidence Genetic analysis of fission yeast alp4 mutants, Mad2 checkpoint assays, and live imaging of Sid1 kinase localization

    PMID:11952833

    Open questions at the time
    • Single-lab fission yeast data
    • Direct molecular link between Alp4 loss and premature SIN activation not established
  6. 2004 Medium

    Mapped the physical interface between the TUBGCP2 ortholog and gamma-tubulin, defining a specific contact surface required for complex assembly.

    Evidence Allele-specific suppressor genetics with mutation mapping, gel filtration, and immunoprecipitation in fission yeast

    PMID:15280226

    Open questions at the time
    • Surface defined genetically rather than by structure
    • Functional consequence of increased complex stability not fully characterized
  7. 2006 Medium

    Revealed that the C-terminal domain regulates cytoplasmic microtubule dynamics and SPB-driven nuclear movement independent of motor proteins.

    Evidence Overexpression of Alp4 C-terminal fragment, live-cell imaging, and genetic deletion of dynein/kinesin motors in fission yeast

    PMID:16611238

    Open questions at the time
    • Effect studied via overexpression fragment, not endogenous protein
    • Mechanism of MT stabilization by the C-terminal domain unknown
  8. 2006 Medium

    Distinguished compartment-specific functions of the gamma-tubulin complex, showing nuclear versus cytoplasmic pools have distinct roles in spindle assembly, cell-cycle timing, and polarity.

    Evidence NLS/NES-tagged Alp4 C-terminal fragments, fractionation, live imaging, flow cytometry, and immunofluorescence in fission yeast

    PMID:16611237

    Open questions at the time
    • Based on targeted fragment overexpression
    • Relevance of nuclear/cytoplasmic partitioning to human GCP2 not tested
  9. 2013 Medium

    Identified the N-terminal domain of human GCP2 as a determinant of competitive incorporation into the large gamma-TuRC.

    Evidence Cross-species genetic complementation, sucrose gradient fractionation, and chimeric Alp4-GCP2 protein assays

    PMID:23886939

    Open questions at the time
    • Molecular basis of N-terminal exclusion from the >2000 kDa complex not resolved
    • Single-lab heterologous system
  10. 2019 Medium

    Linked TUBGCP2 loss-of-function to human disease, establishing gamma-TuRC integrity as essential for neuronal migration and cortical development.

    Evidence Exome sequencing of multiple families with microcephaly/lissencephaly, GeneMatcher, and brain MRI phenotyping

    PMID:31630790

    Open questions at the time
    • No in vitro reconstitution of variant effects
    • Mechanism by which variants impair neuronal migration not directly tested
  11. 2020 Low

    Provided cellular evidence that a disease variant predicted to disrupt the GCP2-GCP3 interaction perturbs gamma-tubulin localization and downstream cytoskeletal/adhesion/axon-guidance proteomes.

    Evidence Patient primary fibroblast immunofluorescence for gamma-tubulin and mass spectrometry proteomics

    PMID:33458610

    Open questions at the time
    • Single patient fibroblast study without direct validation of GCP2-GCP3 disruption
    • Causality between proteome changes and the variant not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How specific human TUBGCP2 variants alter gamma-TuRC assembly, microtubule nucleation kinetics, and neuronal migration at the molecular level remains unresolved.
  • No structural model of variant effects on the human complex
  • No in vitro reconstitution linking variants to nucleation defects
  • No neuronal-migration assay directly testing patient mutations

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005856 cytoskeleton 2 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-1640170 Cell Cycle 2 R-HSA-1266738 Developmental Biology 1
Partners
SPC110PSPC98PTUB4PTUBG1TUBGCP3
Complex memberships
gamma-tubulin ring complex (gamma-TuRC)gamma-tubulin small complex (gamma-TuSC)

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Spc97p (yeast ortholog of TUBGCP2) forms a 6S complex with Tub4p (gamma-tubulin) and Spc98p, containing one molecule each of Spc98p and Spc97p and two or more molecules of Tub4p, with no other proteins. Purification of the Tub4p complex; sucrose gradient fractionation; immunoprecipitation The EMBO journal High 9384578
1997 Spc97p (yeast ortholog of TUBGCP2) and Spc98p mediate binding of the gamma-tubulin (Tub4p) complex to the spindle pole body via their interaction with the N-terminal domain of Spc110p. Genetic suppression analysis; biochemical pulldown; two-hybrid interaction; immunoprecipitation The EMBO journal High 9130700 9384578
1997 Spc97p (yeast ortholog of TUBGCP2) physically interacts with both Tub4p (gamma-tubulin) and Spc98p, and this trimeric complex is required for microtubule organization and SPB duplication; temperature-sensitive spc97 alleles cause spindle defects including failure in SPB separation, spindle formation, and SPB duplication. Two-hybrid interaction; immunoprecipitation; fractionation; genetic suppression (high-copy SPC98 or TUB4 suppresses spc97 ts alleles); overexpression toxicity assays The EMBO journal High 9130700
1998 Human GCP2 (hGCP2/TUBGCP2) and GCP3 are homologs of yeast Spc97p and Spc98p; they are components of the mammalian gamma-tubulin complex, colocalize with gamma-tubulin at the centrosome, and co-sediment with gamma-tubulin in sucrose gradients. Stable cell lines expressing epitope-tagged gamma-tubulin; immunoprecipitation; sucrose gradient cosedimentation; colocalization by immunofluorescence; sequence analysis The Journal of cell biology High 9566967
2002 Alp4 (fission yeast ortholog of TUBGCP2) is required for recruitment of the gamma-tubulin complex to the spindle pole body; loss of Alp4 function causes bipolar spindle defects and activates the Mad2 checkpoint, yet untimely activation of the SIN (septation initiation network) drives septation despite monopolar spindles, with Sid1 kinase recruited prematurely to both SPBs instead of one. Genetic analysis of alp4 mutants; checkpoint activation assays; live-cell imaging of Sid1 kinase localization; cyclin B level measurements at SPB Genes to cells : devoted to molecular & cellular mechanisms Medium 11952833
2004 In fission yeast, Alp4 (TUBGCP2 ortholog) directly interacts with gamma-tubulin (Gtb1); allele-specific suppressors of alp4 mutations map to a small surface region of gamma-tubulin, defining the Alp4-binding interface on gamma-tubulin. Mutant complexes showed altered (increased) stability. Allele-specific suppressor genetics; mutation mapping; gel filtration; immunoprecipitation Genetics Medium 15280226
2006 Overproduction of the C-terminal domain of Alp4 (TUBGCP2 ortholog) in fission yeast alters microtubule dynamics, stabilizing cytoplasmic microtubules, and induces oscillatory nuclear movement via SPB-driven MT pushing forces; this movement depends on microtubule stability rather than dynein or kinesin motors. Overexpression of Alp4 C-terminal fragment; live-cell imaging; SPB/MT dynamics measurements; genetic analysis (deletion of dhc1, pkl1, klp2) Genes to cells : devoted to molecular & cellular mechanisms Medium 16611238
2006 Nuclear-localized C-terminal Alp4 (TUBGCP2 ortholog) induces Wee1-dependent G2 delay, reduces gamma-tubulin complex levels at the SPB, and causes defects in spindle assembly, cytoplasmic microtubule disassembly, and chromosome segregation; cytoplasmic Alp4C induces nuclear oscillation and affects cell polarity markers Bud6 and Tip1. This demonstrates distinct functions for nuclear versus cytoplasmic gamma-tubulin complexes. Overexpression of NLS- and NES-tagged Alp4 C-terminal fragments; subcellular fractionation; live-cell imaging; flow cytometry; immunofluorescence Genes to cells : devoted to molecular & cellular mechanisms Medium 16611237
2013 Human GCP2 (TUBGCP2) can functionally replace fission yeast Alp4 for essential vegetative functions, but its N-terminal domain limits full displacement of Alp4 during gamma-TuRC assembly; when Alp4 is present, GCP2 is excluded from the >2000 kDa gamma-TuRC and fractionates as smaller complexes. A chimeric Alp4-GCP2 protein demonstrated the N-terminal domain of GCP2 as the limiting feature. Cross-species genetic complementation; sucrose gradient fractionation; biochemical analysis of complex incorporation; chimeric protein construction and functional assay Journal of cell science Medium 23886939
2019 Bi-allelic pathogenic variants in TUBGCP2 (p.Arg333Cys, p.Ala615Pro, p.Arg297Cys, and a splice variant) cause autosomal recessive microcephaly and lissencephaly spectrum disorders in humans, implicating GCP2 as a core component of gamma-TuRC required for neuronal migration. Exome sequencing; family-based rare variant analysis; GeneMatcher collaboration; brain MRI imaging for cortical malformation phenotyping American journal of human genetics Medium 31630790
2020 A homozygous TUBGCP2 variant (p.Glu311Lys), predicted to disrupt electrostatic interaction of GCP2 with GCP3, causes faint delocalization of gamma-tubulin during the cell cycle in patient fibroblasts and dysregulation of proteins involved in cytoskeletal assembly, cellular adhesion, and axon guidance, as detected by mass spectrometry proteomics. Patient primary fibroblast analysis; immunofluorescence for gamma-tubulin localization; mass spectrometry proteomics iScience Low 33458610

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Spc98p and Spc97p of the yeast gamma-tubulin complex mediate binding to the spindle pole body via their interaction with Spc110p. The EMBO journal 201 9384578
1998 The mammalian gamma-tubulin complex contains homologues of the yeast spindle pole body components spc97p and spc98p. The Journal of cell biology 178 9566967
1997 The spindle pole body component Spc97p interacts with the gamma-tubulin of Saccharomyces cerevisiae and functions in microtubule organization and spindle pole body duplication. The EMBO journal 175 9130700
2002 The gamma-tubulin complex protein Alp4 provides a link between the metaphase checkpoint and cytokinesis in fission yeast. Genes to cells : devoted to molecular & cellular mechanisms 31 11952833
2019 Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders. American journal of human genetics 28 31630790
2004 Functional dissection of the gamma-tubulin complex by suppressor analysis of gtb1 and alp4 mutations in Schizosaccharomyces pombe. Genetics 20 15280226
2006 The carboxy-terminus of Alp4 alters microtubule dynamics to induce oscillatory nuclear movement led by the spindle pole body in Schizosaccharomyces pombe. Genes to cells : devoted to molecular & cellular mechanisms 15 16611238
2020 Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease. iScience 12 33458610
2006 Modulation of Alp4 function in Schizosaccharomyces pombe induces novel phenotypes that imply distinct functions for nuclear and cytoplasmic gamma-tubulin complexes. Genes to cells : devoted to molecular & cellular mechanisms 10 16611237
2013 Functional replacement of fission yeast γ-tubulin small complex proteins Alp4 and Alp6 by human GCP2 and GCP3. Journal of cell science 5 23886939
2025 TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review. Frontiers in pediatrics 1 40017707
2025 Thick Corpus Callosum: An Unusual Finding of TUBGCP2-Related Tubulinopathy. American journal of medical genetics. Part A 1 40448381

Missed literature

Know a paper Affinage missed for TUBGCP2? Flag it for the maintainers and the community.

No submissions yet.