Affinage

OST4

Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 4 · UniProt P0C6T2

Length
37 aa
Mass
4.2 kDa
Annotated
2026-06-10
28 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

OST4 encodes an unusually small (~3.6 kDa, 36-residue) single-pass ER membrane protein that functions as a structural subunit of the oligosaccharyltransferase (OST) complex required for efficient co-translational N-glycosylation in both yeast and mammals (PMID:8621712, PMID:9405463). In yeast, Ost4p is an equimolar subunit of the eight-subunit OST and adopts an N(lumen)-C(cytosol) type I topology, with its cytoplasmic-leaflet transmembrane residues (~18-25) physically bridging the catalytic Stt3 subunit to the accessory subunit Ost3p; mutation of these residues to ionizable amino acids severs both the Ost4-Stt3 and the Ost3-Stt3 contacts (PMID:9405463, PMID:12810948). Ost4p is required for assembly of two functionally distinct OST isoforms, since loss of Ost4p prevents incorporation of either Ost3p or Ost6p into the complex (PMID:16096346). The human ortholog assembles into both STT3A- and STT3B-containing OST complexes and contacts ribophorin I; a single transmembrane substitution or siRNA depletion of OST4 destabilizes native complexes and reduces N-glycosylation of endogenous substrate, paralleling the yeast role in stabilizing the assembled catalytic core (PMID:23606741). Structurally, the destabilizing V23D substitution exposes a charged residue in the membrane and disrupts hydrophobic helix-helix packing against Stt3 transmembrane segments TM12/TM13, explaining how a point mutation disassembles the complex (PMID:33442744). When mislocalized to the outer mitochondrial membrane, Ost4 is recognized and extracted by the AAA+ ATPase Msp1 irrespective of its membrane orientation (PMID:40236206).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1996 High

    Established that the OST4 gene product, despite its tiny size, is functionally required for normal oligosaccharyltransferase activity, defining it as a genuine OST component rather than an incidental polypeptide.

    Evidence Null-mutant genetics with in vivo and in vitro OTase activity assays in yeast

    PMID:8621712

    Open questions at the time
    • Did not resolve whether Ost4 acts catalytically or structurally
    • No subunit-contact map defined
  2. 1997 High

    Defined Ost4p as a stoichiometric OST subunit and localized its position within the complex, showing it bridges the catalytic Stt3p to the accessory Ost3p subunit.

    Evidence Co-immunoprecipitation of all subunits with quantitative stoichiometry and partial-denaturation subcomplex isolation in yeast

    PMID:9405463

    Open questions at the time
    • The molecular interface mediating bridging was not mapped
    • Topology of Ost4p unknown
  3. 1997 Medium

    Provided genetic confirmation that Ost4p functionally interacts with the catalytic Stt3p subunit, independent of biochemical co-purification.

    Evidence Suppression of conditional stt3 alleles by OST4 overexpression in yeast

    PMID:9435788

    Open questions at the time
    • Genetic epistasis does not establish a direct physical contact
    • Single method, single lab
  4. 2003 High

    Mapped Ost4p topology and identified the specific cytoplasmic-leaflet transmembrane residues whose integrity is needed to hold Stt3p and Ost3p together, converting the bridging model into residue-level mechanism.

    Evidence In vivo topology mapping, transmembrane mutagenesis, CD of synthetic peptide in liposomes, and Co-IP in ost4 mutant backgrounds

    PMID:12810948

    Open questions at the time
    • No high-resolution structure of the contact
    • Did not address mammalian conservation
  5. 2005 High

    Demonstrated that Ost4p is required for biogenesis of both the Ost3p- and Ost6p-containing OST isoforms, broadening its role from a single complex to assembly of functionally distinct OST forms.

    Evidence Blue native PAGE of OST complexes from wild-type and ost4 deletion strains with subunit immunodetection

    PMID:16096346

    Open questions at the time
    • Functional differences between the two isoforms not attributed to Ost4 directly
    • Order of assembly events unresolved
  6. 2011 Medium

    Provided the first structural view of human OST4, showing an α-helical transmembrane segment with a kink.

    Evidence Solution NMR of human OST4 in detergent

    PMID:21609714

    Open questions at the time
    • Structure in detergent rather than native bilayer
    • No functional or interaction data in the same study
  7. 2013 High

    Extended the yeast subunit-stabilization model to mammals, showing human OST4 incorporates into both STT3A- and STT3B-containing complexes and stabilizes them to support co-translational N-glycosylation.

    Evidence Co-IP with both STT3 isoforms and ribophorin I, transmembrane mutagenesis, siRNA knockdown with native gel and prosaposin glycosylation assay

    PMID:23606741

    Open questions at the time
    • Precise mammalian subunit interface not resolved at atomic level
    • Substrate specificity consequences beyond prosaposin not characterized
  8. 2021 Medium

    Provided a structural mechanism for OST destabilization by the V23D mutation, showing it disrupts hydrophobic packing against Stt3 TM12/TM13 and exposes a buried charge.

    Evidence Solution NMR of WT and V23D Ost4 plus MD simulation of the membrane-embedded OST complex

    PMID:33442744

    Open questions at the time
    • No reconstituted activity assay confirming functional disengagement
    • Simulation-derived, not experimentally resolved complex
  9. 2024 Medium

    Confirmed in a native-like lipid bilayer that the V23D mutation dramatically alters the transmembrane helix environment, validating membrane-context effects beyond micelles.

    Evidence Magic-angle-spinning solid-state NMR of Ost4 and Ost4V23D in POPC/POPE bilayers

    PMID:38421550

    Open questions at the time
    • No functional activity assay
    • Effect on intact OST complex not directly observed in bilayer
  10. 2025 Medium

    Identified Ost4 as a quality-control substrate, showing that mislocalized Ost4 at mitochondria is extracted by the AAA+ ATPase Msp1 regardless of orientation, linking OST4 biogenesis to membrane-protein surveillance.

    Evidence Msp1-protease chimera substrate trapping, mass spectrometry identification, and topology assay of mislocalized Ost4 (preprint)

    PMID:40236206

    Open questions at the time
    • Preprint, single lab
    • Physiological frequency of Ost4 mislocalization unknown
    • Fate of extracted Ost4 not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How Ost4 acts within the catalytic cycle of an intact, reconstituted OST complex and whether its bridging function modulates glycosylation efficiency at the level of enzyme turnover remain unresolved.
  • No reconstituted activity assay isolating Ost4 contribution
  • No atomic structure of the full Ost4-Stt3-Ost3 interface
  • Physiological consequences of OST4 loss in mammals beyond cell-based glycosylation assays uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 4 GO:0060090 molecular adaptor activity 2
Localization
GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-392499 Metabolism of proteins 2
Complex memberships
oligosaccharyltransferase (OST) complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 OST4 encodes an unusually small 36-amino-acid (~3.6 kDa) protein that is required for normal oligosaccharyltransferase (OTase) activity in yeast; deletion of OST4 greatly diminishes but does not abolish OTase activity in vivo and in vitro, and the null mutant is inviable at 37°C, demonstrating OST4 is an essential OTase subunit or accessory component at high temperature. Genetic disruption/null mutant analysis, in vivo and in vitro OTase activity assays, biochemical characterization of the OST4 gene product The Journal of biological chemistry High 8621712
1997 Ost4p (3.6 kDa) is a bona fide subunit of the yeast oligosaccharyltransferase complex present in equimolar stoichiometry with seven other subunits; mild denaturation of the immunoprecipitated complex releases a stable subcomplex comprising Stt3p, Ost3p, and Ost4p, indicating Ost4p bridges these two subunits within the OST. Epitope-tagging of Ost3p, co-immunoprecipitation of all OST subunits, quantification of radiolabeled subunits, partial denaturation to isolate subcomplexes The Journal of biological chemistry High 9405463
1997 Overexpression of OST4 suppresses conditional stt3 alleles in yeast, providing genetic epistasis evidence that Ost4p functionally interacts with the catalytic Stt3p subunit of the OST complex. Genetic suppressor analysis — overexpression of OST4 in stt3 conditional mutants Molecular & general genetics : MGG Medium 9435788
2003 Ost4p adopts an N(lumen)-C(cyto) type I membrane topology in the ER membrane, with its transmembrane segment spanning residues ~10–25; mutation of residues 18–25 to ionizable amino acids disrupts interactions with both Stt3p and Ost3p, and ost4 temperature-sensitive mutants cause loss of direct Ost3p–Stt3p interaction, demonstrating that the cytoplasmic-leaflet region of Ost4p physically bridges Ost3p and Stt3p in the OST subcomplex. In vivo membrane topology determination, site-directed mutagenesis of transmembrane residues, CD analysis of synthetic Ost4p in liposomes, co-immunoprecipitation in ost4 mutant backgrounds Proceedings of the National Academy of Sciences of the United States of America High 12810948
2005 Ost4p is required for the assembly of two functionally distinct OST complexes in yeast: one containing Ost3p and one containing Ost6p. In the absence of Ost4p, neither Ost3p nor Ost6p is incorporated into the OST complex, showing that Ost4p is essential for the assembly of both OST isoforms. Blue native gel electrophoresis of OST complexes from wild-type and ost4 deletion strains, immunodetection of individual subunits Glycobiology High 16096346
2005 The eukaryotic OST complex in yeast contains Ost4p as one of eight equimolar subunits, and the STT3 subunit is critical for catalytic activity; Ost4p participates in the Stt3p-Ost3p/Ost6p subcomplex. Review synthesizing co-immunoprecipitation, blue native gel, and genetic evidence from multiple laboratories Glycobiology Medium 16317064
2011 Solution NMR of human OST4 in detergent solvent reveals that residues 5–30 adopt an α-helical structure with a kink in the transmembrane domain, providing the first structural characterization of the human OST4 protein. NMR spectroscopy (solution structure determination in detergent) Biochemical and biophysical research communications Medium 21609714
2013 Human OST4 is assembled into native OST complexes containing either the catalytic STT3A or STT3B isoforms; OST4 co-immunoprecipitates with both STT3 isoforms and with ribophorin I; a single amino acid change in the OST4 transmembrane region perturbs these interactions; siRNA depletion of OST4 destabilizes native OST complexes (producing a novel ribophorin I subcomplex) and causes a defect in N-glycosylation of endogenous prosaposin similar to STT3A depletion, consistent with OST4 stabilizing STT3A-containing isoforms for co-translational N-glycosylation. Co-immunoprecipitation, site-directed mutagenesis of transmembrane domain, siRNA knockdown, blue native gel electrophoresis, N-glycosylation assay of endogenous substrate (prosaposin) Journal of cell science High 23606741
2021 NMR solution structures and MD simulations of yeast Ost4 and the V23D mutant show that while the V23D point mutation does not alter the overall helical structure of Ost4, it changes its position and solvent exposure in the membrane-mimetic environment; MD simulations of the membrane-embedded OST complex show that V23D disrupts hydrophobic helix–helix interactions between Ost4 and TM12/TM13 of Stt3, causing disengagement of Ost4V23D and exposure of residue D23 in the hydrophobic pocket, providing a structural mechanism for OST complex destabilization. Solution NMR structure determination (micelles), molecular dynamics simulations of membrane-bound OST complex with WT and V23D Ost4 Glycobiology Medium 33442744
2024 Solid-state NMR of yeast Ost4 and Ost4V23D reconstituted in POPC/POPE lipid bilayers shows significant chemical shift changes upon V23D mutation, indicating a dramatic change in the chemical environment of the transmembrane helix in a native-like lipid bilayer context. Solid-state NMR with magic-angle spinning, reconstitution in lipid bilayers Journal of biomolecular NMR Medium 38421550
2025 Ost4 is a substrate of the AAA+ ATPase Msp1 when mislocalized to mitochondria; an Msp1-protease chimera captures Ost4 as a novel Msp1 substrate by mass spectrometry; topology experiments show that mislocalized Ost4 adopts mixed membrane orientations at mitochondria, and Msp1 extracts mislocalized Ost4 regardless of its orientation. Msp1-protease chimera (substrate trapping), mass spectrometry identification, topology assay of mislocalized Ost4 bioRxivpreprint Medium 40236206

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 An evolving view of the eukaryotic oligosaccharyltransferase. Glycobiology 433 16317064
2015 Characterization of the platelet transcriptome by RNA sequencing in patients with acute myocardial infarction. Platelets 107 26367242
1997 The highly conserved Stt3 protein is a subunit of the yeast oligosaccharyltransferase and forms a subcomplex with Ost3p and Ost4p. The Journal of biological chemistry 78 9405463
1996 The OST4 gene of Saccharomyces cerevisiae encodes an unusually small protein required for normal levels of oligosaccharyltransferase activity. The Journal of biological chemistry 61 8621712
2005 The 3.4-kDa Ost4 protein is required for the assembly of two distinct oligosaccharyltransferase complexes in yeast. Glycobiology 51 16096346
1997 The STT3 protein is a component of the yeast oligosaccharyltransferase complex. Molecular & general genetics : MGG 50 9435788
2008 The yeast oligosaccharyltransferase complex can be replaced by STT3 from Leishmania major. Glycobiology 47 18955371
2003 Determination of the membrane topology of Ost4p and its subunit interactions in the oligosaccharyltransferase complex in Saccharomyces cerevisiae. Proceedings of the National Academy of Sciences of the United States of America 45 12810948
2021 Transcriptomic landscape of blood platelets in healthy donors. Scientific reports 39 34344933
2012 Improvement of N-glycan site occupancy of therapeutic glycoproteins produced in Pichia pastoris. Applied microbiology and biotechnology 39 22569635
2002 Mutants defective in secretory/vacuolar pathways in the EUROFAN collection of yeast disruptants. Yeast (Chichester, England) 35 11870858
2024 Identification and validation of extracellular vesicle reference genes for the normalization of RT-qPCR data. Journal of extracellular vesicles 32 38545822
2013 OST4 is a subunit of the mammalian oligosaccharyltransferase required for efficient N-glycosylation. Journal of cell science 32 23606741
2011 Solution structure of a human minimembrane protein Ost4, a subunit of the oligosaccharyltransferase complex. Biochemical and biophysical research communications 22 21609714
2003 Insight into functional aspects of Stt3p, a subunit of the oligosaccharyl transferase. Evidence for interaction of the N-terminal domain of Stt3p with the protein kinase C cascade. The Journal of biological chemistry 21 14530272
2011 A synthetic heparan sulfate oligosaccharide library reveals the novel enzymatic action of D-glucosaminyl 3-O-sulfotransferase-3a. Molecular bioSystems 16 22116385
2019 An updated view of the oligosaccharyltransferase complex in Plasmodium. Glycobiology 7 30835280
2022 Squalene through Its Post-Squalene Metabolites Is a Modulator of Hepatic Transcriptome in Rabbits. International journal of molecular sciences 4 35456988
2020 1H, 13C, 15N resonance assignments and secondary structure of yeast oligosaccharyltransferase subunit Ost4 and its functionally important mutant Ost4V23D. Biomolecular NMR assignments 3 32328881
2014 [The morphology and molecular bases of damage to the stem cell niche of respiratory acini in idiopathic interstitial pneumonias]. Arkhiv patologii 3 25842923
2024 3,3'-Diindolylmethane disrupts the endoplasmic reticulum and nuclear envelope in Schizosaccharomyces pombe. Biochemical and biophysical research communications 2 39332155
2021 NMR and MD simulations reveal the impact of the V23D mutation on the function of yeast oligosaccharyltransferase subunit Ost4. Glycobiology 1 33442744
2026 Clinically interpretable extracellular vesicle gene model for Non-Invasive liver cancer diagnosis. Scientific reports 0 41691101
2026 Genome-Wide Identification of Genomic Regions Associated with Body Weight and Morphometric Traits in Awassi Sheep. Animals : an open access journal from MDPI 0 41897845
2026 Combining multi-omics analysis methods to identify biomarkers for mitophagy involved in immune checkpoint inhibitors-related myocarditis. Frontiers in immunology 0 42093991
2025 An Msp1-Protease Chimera Captures Transient AAA+ Interactions and Unveils Ost4 Mislocalization Errors. bioRxiv : the preprint server for biology 0 40236206
2024 Reconstitution and resonance assignments of yeast OST subunit Ost4 and its critical mutant Ost4V23D in liposomes by solid-state NMR. Journal of biomolecular NMR 0 38421550
1983 [Detection of human osteosarcoma-associated antigens by monoclonal antibodies]. Gan to kagaku ryoho. Cancer & chemotherapy 0 6575722

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