Affinage

GEMIN2

Gem-associated protein 2 · UniProt O14893

Length
280 aa
Mass
31.6 kDa
Annotated
2026-06-10
19 papers in source corpus 17 papers cited in narrative 17 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

GEMIN2 is a core subunit of the SMN complex that imposes specificity and ordered assembly during the biogenesis of spliceosomal U snRNPs (PMID:21816274, PMID:31799625). Structurally, GEMIN2 adopts an extended conformation that wraps around the crescent-shaped SmD1/D2/F/E/G pentamer, contacting all five Sm proteins and reaching into the RNA-binding pocket to block premature RNA access (PMID:21816274); it constrains the pentamer in a narrow state through negative cooperativity with RNA so that snRNA binding allosterically widens the ring and releases GEMIN2/SMN, with subsequent SmD3/B joining completing the handoff (PMID:31799625). GEMIN2 is anchored to a defined helix of SMN, an interaction abolished by an SMA-causing SMN mutation (PMID:21816274, PMID:22607171), and reciprocally SMN stabilizes GEMIN2 protein levels in vivo (PMID:11121410); GEMIN2 in turn self-associates and stabilizes SMN amino-terminal oligomerization, with SMN·GEMIN2 forming dimer-to-octamer assemblies governed by the SMN YG box (PMID:17308308, PMID:26092730). The complex's condensation in Cajal bodies and snRNP output are regulated by p70S6K, which directly binds and phosphorylates GEMIN2 (PMID:37958537). Independently of snRNP assembly, GEMIN2 acts as a RAD51 mediator in homologous recombination: it binds RAD51 directly, inhibits RAD51 dissociation from DNA, and stimulates strand exchange, with the SMN-GEMIN2 complex further enhancing duplex DNA capture, and its depletion reduces recombination efficiency and RAD51 foci (PMID:20403813, PMID:21732698). GEMIN2 also facilitates HIV-1 replication by binding integrase, stabilizing integrase multimers against proteasomal degradation, and promoting reverse transcription (PMID:16731905, PMID:19915660). Genetic dissociation in zebrafish shows that GEMIN2 reduction, unlike SMN loss, does not directly cause motor axon defects (PMID:18000835).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2000 Medium

    Established that GEMIN2 is an obligate partner of SMN in vivo, framing it as a stable component of the SMN complex rather than an independent factor.

    Evidence Tet-repressible SMN disruption in DT40 cells with western blotting for GEMIN2 levels

    PMID:11121410

    Open questions at the time
    • Did not define GEMIN2's molecular contribution to the complex
    • Stabilization mechanism not resolved structurally
  2. 2002 Medium

    Linked reduced Smn/Gemin2 dosage to a snRNP-assembly defect and motoneuron degeneration, connecting the complex to SMA-relevant pathology.

    Evidence Gemin2 heterozygous knockout mice crossed to Smn heterozygotes, Sm protein localization and motoneuron histology

    PMID:12091709

    Open questions at the time
    • Correlative link between snRNP defect and neurodegeneration
    • Cell-autonomy in motoneurons not tested
  3. 2006 Medium

    Identified a non-canonical role for GEMIN2 in HIV-1 biology by showing it binds viral integrase and is required for early infection.

    Evidence Yeast two-hybrid, siRNA depletion in macrophages, HIV-1 infection and viral cDNA assays, co-IP

    PMID:16731905

    Open questions at the time
    • Mechanism by which GEMIN2 aids cDNA synthesis not defined here
    • Co-IP with viral genome indirect
  4. 2007 Medium

    Showed GEMIN2 self-associates and stabilizes SMN oligomers, providing a mechanism for how it promotes assembly-competent SMN complexes.

    Evidence Mammalian two-hybrid, in vitro pull-down and dissociation assays, siRNA knockdown with snRNP assembly readout

    PMID:17308308

    Open questions at the time
    • Structural basis of self-association not determined
    • Stoichiometry of oligomers unresolved at this stage
  5. 2008 Medium

    Dissociated GEMIN2 from SMN's motor axon function by demonstrating cell-autonomous GEMIN2 knockdown does not cause axon defects, separating snRNP assembly from the axonal phenotype.

    Evidence Morpholino and cell-autonomous knockdown plus neuron transplantation in zebrafish, motor axon imaging

    PMID:18000835

    Open questions at the time
    • Negative result; residual GEMIN2 function not excluded
    • Does not address mammalian motoneurons
  6. 2009 Medium

    Defined the mechanism of GEMIN2's pro-viral role: it stabilizes integrase multimers against proteasomal degradation and promotes reverse transcription.

    Evidence In vitro reverse transcription assays, co-IP, synthetic peptide inhibition, proteasome inhibitor experiments

    PMID:19915660

    Open questions at the time
    • Structural detail of IN-GEMIN2 contact unknown
    • Relevance to integrated provirus stages not addressed
  7. 2010 High

    Established GEMIN2 as a direct RAD51 mediator in homologous recombination, expanding its role beyond snRNP assembly.

    Evidence Direct binding assays, in vitro recombination assays, siRNA and knockout cells, RAD51 focus assays

    PMID:20403813

    Open questions at the time
    • Whether HR role depends on the full SMN complex not resolved here
    • In vivo HR contribution in differentiated cells unclear
  8. 2010 Medium

    Placed GEMIN2 in cytoplasmic U bodies and in mRNA-associated complexes, indicating subcellular contexts for its activity.

    Evidence Immunofluorescence in Drosophila egg chambers; IP of SMN/Gemin2/Gemin3 complexes with RT-PCR for beta-actin mRNA in neuroblastoma cells

    PMID:20452345 PMID:20620147

    Open questions at the time
    • Functional consequence of mRNA association unknown
    • Direct vs indirect mRNA binding not distinguished
  9. 2011 High

    Provided the atomic-resolution mechanism for GEMIN2's specificity function: it wraps the Sm pentamer and occludes the RNA-binding pocket, and an SMA mutation disrupts SMN-GEMIN2 binding.

    Evidence 2.5 A crystal structure of Gemin2-pentamer-SMN, structure-guided mutagenesis, binding assays

    PMID:21816274

    Open questions at the time
    • Did not capture the RNA-bound release intermediate
    • Dynamics of the assembly transition inferred not observed
  10. 2011 High

    Showed the SMN-GEMIN2 complex outperforms GEMIN2 alone in HR by conferring DNA-binding and stimulating duplex capture, integrating the two activities.

    Evidence Purified SMN-GEMIN2 fusion, in vitro recombination and DNA-binding assays, knockout complementation

    PMID:21732698

    Open questions at the time
    • Physiological SMN-GEMIN2 stoichiometry at DSBs unknown
    • Relationship to snRNP pool not defined
  11. 2012 High

    Refined the SMN-GEMIN2 interface and identified a conserved SMN/GEMIN2 surface, distinct from the binding contact, likely needed for assembly.

    Evidence NMR solution structure of GEMIN2 bound to SMN GEMIN2-binding domain, mutagenesis

    PMID:22607171

    Open questions at the time
    • Functional role of the conserved surface not directly tested
    • SMA mutation effects on assembly not measured here
  12. 2015 High

    Defined the oligomeric architecture of SMN·GEMIN2 and the SMN YG box as the necessary and sufficient oligomerization determinant, conserved from yeast to human.

    Evidence 1.9 A crystal structure of yeast SMN YG box, analytical ultracentrifugation, disulfide cross-linking, SEC

    PMID:26092730

    Open questions at the time
    • Functional output of higher-order oligomers in assembly not quantified
    • Regulation of oligomer state not addressed
  13. 2016 Medium

    Defined which Sm ring subunits genetically require the GEMIN2 ortholog Brr1, mapping the assembly steps that depend on GEMIN2.

    Evidence Yeast synthetic lethality screen and complementation with Sm and Brr1 mutants

    PMID:27974620

    Open questions at the time
    • Yeast genetics may not fully reflect human assembly order
    • Biochemical reconstitution of the subset dependence not shown
  14. 2020 High

    Revealed the allosteric logic of snRNP assembly: GEMIN2 enforces a narrow pentamer state via negative cooperativity with RNA, and RNA binding widens the ring to release GEMIN2/SMN.

    Evidence X-ray crystallography, biochemical binding and assembly assays, mutational analysis

    PMID:31799625

    Open questions at the time
    • Kinetics of the release transition in cells not measured
    • Coupling to downstream snRNP maturation not detailed
  15. 2023 Medium

    Identified upstream regulation of GEMIN2 by p70S6K phosphorylation controlling SMN complex condensation in Cajal bodies and snRNP output.

    Evidence Co-IP, in vitro kinase assay, SEC, p70S6K knockdown, Cajal body counting

    PMID:37958537

    Open questions at the time
    • Phosphosites and their structural effect not mapped
    • Signaling context driving p70S6K activity not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GEMIN2's distinct roles in snRNP assembly, homologous recombination, and HIV-1 reverse transcription are coordinated, partitioned, or regulated within a cell remains unresolved.
  • No structural model of GEMIN2-RAD51 or GEMIN2-integrase complexes
  • Determinants directing GEMIN2 to HR versus snRNP pools unknown
  • Physiological signals coupling p70S6K regulation to each function undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0003723 RNA binding 2 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-1643685 Disease 2 R-HSA-73894 DNA Repair 2 R-HSA-8953854 Metabolism of RNA 2
Partners
HIV-1 INTEGRASERAD51RPS6KB1SMN1
Complex memberships
SMN complex

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 Crystal structure (2.5 Å) of Gemin2 bound to the SmD1/D2/F/E/G pentamer and SMN's Gemin2-binding domain revealed that Gemin2 adopts an extended conformation wrapping around the crescent-shaped pentamer, interacting with all five Sm proteins, gripping both sides and the outer perimeter, and reaching into the RNA-binding pocket to prevent RNA binding. An SMA-causing mutation in an SMN helix that mediates Gemin2 binding abrogates SMN-Gemin2 interaction. X-ray crystallography (2.5 Å), structure-guided mutagenesis, biochemical binding assays Cell High 21816274
2020 Crystallographic and biochemical analyses showed that Gemin2 constrains the horseshoe-shaped SmD1/D2/F/E/G pentamer in a narrow state via negative cooperativity with RNA, enhancing RNA specificity. RNA binding inside the pentamer widens it, allosterically releasing Gemin2/SMN; subsequent SmD3/B joining further facilitates Gemin2/SMN release. This reveals the mechanism of snRNA selection and SMN complex release during snRNP assembly. X-ray crystallography, biochemical binding and assembly assays, mutational analysis Nucleic acids research High 31799625
2012 NMR solution structure of Gemin2 bound to the Gemin2-binding domain of SMN revealed how Gemin2 is stabilized by SMN and identified conserved SMN residues at the binding interface. Notably, several conserved SMN residues including sites of two SMA patient mutations are not required for Gemin2 binding but form a conserved SMN/Gemin2 surface likely important for snRNP assembly. NMR spectroscopy, biochemical binding assays The Biochemical journal High 22607171
2010 Human GEMIN2 directly binds RAD51 and stimulates RAD51-mediated homologous pairing by inhibiting RAD51 dissociation from DNA and enhancing the RAD51-mediated strand exchange when RPA is pre-bound to ssDNA. Depletion of GEMIN2 in chicken DT40 cells and human cells reduced homologous recombination efficiency and decreased RAD51 subnuclear foci formation, establishing GEMIN2 as a novel RAD51 mediator. Biochemical binding assays (direct binding), in vitro recombination assays, siRNA knockdown, RAD51 focus formation assay, GEMIN2-knockout cell line Nucleic acids research High 20403813
2011 The purified SMN-GEMIN2 fusion complex stimulates RAD51-mediated homologous pairing more efficiently than GEMIN2 alone. SMN-GEMIN2, but not GEMIN2 alone, possesses DNA-binding activity and significantly stimulates secondary duplex DNA capture by the RAD51-ssDNA complex during homologous pairing, establishing a role for the SMN-GEMIN2 complex in homologous recombination. Protein purification, in vitro recombination and DNA-binding assays, complementation of GEMIN2-knockout cells Biochemistry High 21732698
2007 Gemin2 undergoes self-association (homodimerization) detected by mammalian two-hybrid and in vitro pull-down assays. Gemin2 stabilizes SMN oligomer formation; in vitro dissociation assays showed that Gemin2 presence stabilizes SMN amino-terminal self-interaction. Gemin2 knockdown by siRNA drastically decreases SMN oligomer formation and snRNP assembly activity. Mammalian two-hybrid, in vitro pull-down, in vitro dissociation assay, siRNA knockdown, snRNP assembly assay The Journal of biological chemistry Medium 17308308
2000 Depletion of SMN protein in DT40 cells leads to a significant decrease in Gemin2 protein levels, demonstrating that SMN stabilizes Gemin2 and that SMN and Gemin2 form a stable complex in vivo. Tet-repressible SMN expression system in DT40 cells (homologous recombination-based SMN gene disruption), western blotting The Journal of biological chemistry Medium 11121410
2002 In vivo genetic evidence that reduced Smn/Gemin2 protein levels disturb U snRNP assembly (indicated by reduced nuclear accumulation of Sm proteins) and that this correlates with enhanced motoneuron degeneration in Gemin2(+/-)/Smn(+/-) double heterozygous mice. Mouse gene targeting (Gemin2 heterozygous knockout), Sm protein localization by immunofluorescence, histological assessment of motoneuron degeneration Proceedings of the National Academy of Sciences of the United States of America Medium 12091709
2006 GEMIN2/SIP1 binds HIV-1 integrase (IN), identified by yeast two-hybrid, and siRNA depletion of Gemin2 in human monocyte-derived macrophages dramatically reduces HIV-1 infection and viral cDNA synthesis without affecting expression from integrated proviral DNA. Co-immunoprecipitation suggested Gemin2 interacts with the incoming viral genome through IN. Yeast two-hybrid, siRNA knockdown, HIV-1 infection assay, co-immunoprecipitation with FLAG-tagged Gemin2 Journal of virology Medium 16731905
2009 Gemin2/SIP1 stabilizes HIV-1 integrase (IN) multimer formation by preventing proteasome-mediated degradation of IN. The SMN-interacting protein 1 (SIP1/Gemin2)-IN interaction promotes assembly of IN and reverse transcriptase on viral RNA, augmenting reverse transcriptase activity in vitro. Synthetic peptides mimicking IN binding motifs that disrupt IN-SIP1 interaction abrogated reverse transcription in vitro and in vivo. In vitro reverse transcription assay, siRNA knockdown, co-immunoprecipitation, synthetic peptide inhibition, proteasome inhibitor experiments PloS one Medium 19915660
2015 SMN·Gemin2 complexes from humans form oligomers spanning the dimer-to-octamer range, with the YG box oligomerization domain of SMN being both necessary and sufficient for oligomerization. Fission yeast SMN·Gemin2 exists as a dimer-tetramer equilibrium (Kd = 1.0 ± 0.9 µM). A 1.9 Å crystal structure of the yeast SMN YG box confirmed high structural conservation with the human ortholog. Disulfide cross-linking showed SMN tetramers form by self-association of stable dimers. X-ray crystallography (1.9 Å), analytical ultracentrifugation, disulfide cross-linking, size-exclusion chromatography The Journal of biological chemistry High 26092730
2010 Drosophila Gemin2 (CG10419) colocalizes with SMN in cytoplasmic U bodies in Drosophila egg chambers. Gemin2 is excluded from P bodies but consistently found associated with them due to the invariant U body–P body association. Immunofluorescence/confocal microscopy in Drosophila egg chambers Experimental cell research Medium 20452345
2010 SMN, Gemin2 and Gemin3 associate with beta-actin mRNA in cytoplasmic complexes in human SHSY5Y neuroblastoma cells, providing the first direct evidence of beta-actin mRNA in SMN cytoplasmic complexes. Targeted mRNA screen (immunoprecipitation of SMN/Gemin2/Gemin3 complexes followed by RT-PCR for beta-actin mRNA) Journal of molecular biology Medium 20620147
2008 Gemin2 knockdown specifically in motoneurons in zebrafish using two separate approaches (cell-autonomous knockdown) did not cause motor axon outgrowth defects, in contrast to SMN knockdown. Motor axon defects observed with global Gemin2 morpholino knockdown were secondary to body morphology defects, as shown by wild-type neuron transplantation experiments. This establishes that Gemin2 reduction does not directly cause motor axon phenotypes, dissociating snRNP function from SMN's motor axon role. Morpholino knockdown in zebrafish, cell-autonomous knockdown in motoneurons, neuronal transplantation assay, motor axon imaging Developmental neurobiology Medium 18000835
2023 p70S6 kinase (ribosomal protein S6 kinase beta-1, p70S6K) directly binds and phosphorylates Gemin2. The phosphorylation status of Gemin2 influences the capacity of the SMN complex to condense in Cajal bodies in vivo. p70S6K knockdown reduced the number of Cajal bodies and inhibited in vivo UsnRNP synthesis. Gemin2 also functions as a connecting element between the 6S complex and the SMN complex, as shown by size exclusion chromatography. Co-immunoprecipitation, in vitro kinase assay (p70S6K phosphorylating Gemin2), size exclusion chromatography, siRNA knockdown of p70S6K, Cajal body counting by immunofluorescence International journal of molecular sciences Medium 37958537
2006 C. elegans SMI-1 (orthologue of Gemin2) directly interacts with SMN-1 protein, shown by yeast two-hybrid and demonstrated conservation of the SMN-Gemin2 interaction in C. elegans. Yeast two-hybrid, cloning and sequencing of smi-1, RNAi phenotypic analysis Invertebrate neuroscience : IN Low 16964508
2016 In S. cerevisiae, the Gemin2 homolog Brr1 is required for snRNP Sm ring assembly in specific Sm protein mutant backgrounds. The N-terminal segment of Brr1 (amino acids 24-47) corresponding to the Gemin2 α1 helix that interacts with SmF, and a C-terminal peptide (336QKDLIE341) that in Gemin2 interacts with SmD2, are essential for Brr1 function. Specific SmE, SmF, SmD2, and SmD1 subunit mutations are synthetically lethal with brr1Δ, but not SmG, SmD3, and SmB mutations, defining the subset of the ring that requires Brr1/Gemin2 for assembly. Yeast genetics (synthetic lethality screen, complementation assay), site-directed mutagenesis of Sm proteins and Brr1 RNA (New York, N.Y.) Medium 27974620

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Structure of a key intermediate of the SMN complex reveals Gemin2's crucial function in snRNP assembly. Cell 107 21816274
2002 Gene targeting of Gemin2 in mice reveals a correlation between defects in the biogenesis of U snRNPs and motoneuron cell death. Proceedings of the National Academy of Sciences of the United States of America 67 12091709
2000 A cell system with targeted disruption of the SMN gene: functional conservation of the SMN protein and dependence of Gemin2 on SMN. The Journal of biological chemistry 52 11121410
2007 Gemin2 plays an important role in stabilizing the survival of motor neuron complex. The Journal of biological chemistry 49 17308308
2006 Identification of a novel human immunodeficiency virus type 1 integrase interactor, Gemin2, that facilitates efficient viral cDNA synthesis in vivo. Journal of virology 49 16731905
2010 Drosophila SMN complex proteins Gemin2, Gemin3, and Gemin5 are components of U bodies. Experimental cell research 37 20452345
2010 GEMIN2 promotes accumulation of RAD51 at double-strand breaks in homologous recombination. Nucleic acids research 33 20403813
2009 Augmentation of reverse transcription by integrase through an interaction with host factor, SIP1/Gemin2 Is critical for HIV-1 infection. PloS one 29 19915660
2010 SMN, Gemin2 and Gemin3 associate with beta-actin mRNA in the cytoplasm of neuronal cells in vitro. Journal of molecular biology 28 20620147
2015 Oligomeric Properties of Survival Motor Neuron·Gemin2 Complexes. The Journal of biological chemistry 27 26092730
2008 The SMN binding protein Gemin2 is not involved in motor axon outgrowth. Developmental neurobiology 24 18000835
2012 Solution structure of the core SMN-Gemin2 complex. The Biochemical journal 22 22607171
2011 Purification of the human SMN-GEMIN2 complex and assessment of its stimulation of RAD51-mediated DNA recombination reactions. Biochemistry 19 21732698
2006 Caenorhabditis elegans in the study of SMN-interacting proteins: a role for SMI-1, an orthologue of human Gemin2 and the identification of novel components of the SMN complex. Invertebrate neuroscience : IN 19 16964508
2020 Negative cooperativity between Gemin2 and RNA provides insights into RNA selection and the SMN complex's release in snRNP assembly. Nucleic acids research 13 31799625
2016 Will the circle be unbroken: specific mutations in the yeast Sm protein ring expose a requirement for assembly factor Brr1, a homolog of Gemin2. RNA (New York, N.Y.) 8 27974620
2024 Interaction between MARK3 (rs11623869), PLCB4 (rs6086746) and GEMIN2 (rs2277458) variants with bone mineral density and serum 25-hidroxivitamin D levels in Mexican Mestizo women. Frontiers in endocrinology 2 38715801
2013 The gemin2-binding site on SMN protein: accessibility to antibody. Biochemical and biophysical research communications 1 23939045
2023 The Impact of p70S6 Kinase-Dependent Phosphorylation of Gemin2 in UsnRNP Biogenesis. International journal of molecular sciences 0 37958537

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