Affinage

DPM3

Dolichol-phosphate mannosyltransferase subunit 3 · UniProt Q9P2X0

Length
92 aa
Mass
10.1 kDa
Annotated
2026-06-09
36 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

DPM3 is an essential non-catalytic subunit of the trimeric ER-localized Dol-P-Man (DPM) synthase complex, where it physically bridges the regulatory subunit DPM2 and the catalytic subunit DPM1 to control production of the mannosyl donor Dol-P-Man (PMID:10835346). Through a coiled-coil domain near its C-terminus, DPM3 tethers DPM1 to the ER membrane and stabilizes it; in the absence of DPM3, DPM1 is rapidly degraded by the proteasome after association with the chaperone-dependent E3 ubiquitin ligase CHIP, and DPM synthase activity together with downstream GPI-anchor biosynthesis is abolished (PMID:16280320). DPM2 stabilizes DPM3 while DPM3 in turn stabilizes DPM1, establishing a hierarchical assembly in which DPM3 is the central structural linchpin (PMID:10835346). Because DPM-derived Dol-P-Man feeds all four Dol-P-Man-dependent ER glycosylation pathways, loss or weakening of DPM3 disproportionately impairs O-mannosylation of alpha-dystroglycan in skeletal muscle, and N-glycosylation of beta-dystroglycan is also affected (PMID:19576565, PMID:30931530). Hypomorphic missense mutations in the DPM3 coiled-coil domain (p.L85S, p.Leu44Pro) that reduce DPM1 binding or DPM synthase activity cause a congenital disorder of glycosylation presenting as muscular dystrophy (PMID:19576565, PMID:28803818); depletion of dpm3 in zebrafish reproduces muscle disorganization and alpha-dystroglycan hypoglycosylation in vivo (PMID:27291147).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2000 High

    Established that human DPM synthase is a trimeric complex and defined DPM3 as the bridging subunit that contacts DPM1 via its C-terminus and DPM2 via its N-terminus, resolving how the enzyme is assembled and stabilized.

    Evidence Complementation of DPM2-null Lec15 cells, co-purification of subunits, and functional DPM biosynthesis assay

    PMID:10835346

    Open questions at the time
    • No structural model of the trimeric interface
    • Stoichiometry of the complex not directly determined
    • Did not address proteasomal turnover route of unassembled subunits
  2. 2005 High

    Demonstrated DPM3 is strictly required for enzyme activity and that its C-terminal coiled-coil tethers DPM1 to the ER membrane, while loss of DPM3 routes free DPM1 to CHIP-mediated proteasomal degradation, defining the molecular basis of DPM3-dependent DPM1 stabilization.

    Evidence DPM3-deficient CHO2.38 cell line, domain deletion/mutagenesis, DPM synthase and GPI-anchor assays, and co-immunoprecipitation with CHIP plus proteasome inhibition

    PMID:16280320

    Open questions at the time
    • Direct ubiquitination of DPM1 by CHIP not reconstituted in vitro
    • Function of the two N-terminal transmembrane regions undefined
    • Whether other E3 ligases contribute not addressed
  3. 2009 High

    Connected DPM3 dysfunction to human disease by showing a coiled-coil domain missense mutation weakens DPM1 binding, lowers DPM synthase activity, and reduces alpha-dystroglycan O-mannosylation, explaining the muscular dystrophy phenotype.

    Evidence Sanger sequencing, CHO2.38 complementation, DPM3-DPM1 binding assay, enzyme activity assay, and muscle biopsy immunohistochemistry

    PMID:19576565

    Open questions at the time
    • Why muscle/alpha-dystroglycan is preferentially affected over other pathways not mechanistically resolved
    • Quantitative threshold of residual activity for disease not defined
  4. 2013 Medium

    Showed the DPM3 interaction surface matters reciprocally from the DPM1 side, as a DPM1 mutation reducing DPM3 binding lowers active enzyme amount without impairing catalysis, reinforcing that complex assembly determines enzyme level.

    Evidence Patient fibroblast enzymatic activity with substrate affinity measurement and co-immunoprecipitation of tagged mutant DPM1 with DPM3

    PMID:23856421

    Open questions at the time
    • Co-IP in transfected cells without reciprocal/structural validation
    • Direct effect on DPM3 stability not measured
  5. 2016 Medium

    Provided in vivo confirmation that DPM3 is required for muscle integrity, linking complex activity loss to alpha-dystroglycan hypoglycosylation and muscle apoptosis at the organismal level.

    Evidence Antisense morpholino knockdown of dpm3 in zebrafish with DPM synthase activity, alpha-dystroglycan immunostaining, and apoptosis assays

    PMID:27291147

    Open questions at the time
    • Morpholino off-target effects not excluded by genetic rescue
    • Did not dissect which downstream glycosylation pathway drives the muscle phenotype
  6. 2017 Medium

    Identified an additional hypomorphic DPM3 allele causing ~50% activity loss and limb girdle muscular dystrophy, confirming partial loss of Dol-P-Man supply limits POMT1/2-dependent alpha-dystroglycan O-glycosylation.

    Evidence Exome sequencing, DPM synthase activity in patient cells, and muscle biopsy glycosylation analysis

    PMID:28803818

    Open questions at the time
    • No complementation/rescue of the specific allele
    • Genotype-phenotype severity correlation across alleles not established
  7. 2019 Medium

    Refined the tissue-level glycosylation defect by showing DPM3-CDG impairs both O-mannosylation of alpha-dystroglycan and N-glycosylation of beta-dystroglycan in muscle, broadening the readout beyond alpha-dystroglycan alone.

    Evidence Skeletal muscle biopsy western blot of beta-dystroglycan N-glycan and alpha-dystroglycan immunostaining in three patients

    PMID:30931530

    Open questions at the time
    • Single lab, no functional rescue
    • Mechanistic basis for selective loss of a single beta-dystroglycan N-glycan not determined
  8. 2001 Low

    Reported a context outside glycosylation in which DPM3/prostin-1 expression is modulated by PLCgamma signaling and overexpression triggers apoptosis, raising an unresolved regulatory dimension.

    Evidence Microarray expression analysis, pharmacological PLCgamma inhibition (U73122), and DPM3 overexpression with apoptosis readout in COS cells

    PMID:11420690

    Open questions at the time
    • Non-specific inhibitor and overexpression-driven apoptosis without mechanistic follow-up
    • Link to DPM synthase function not established
    • Not independently confirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DPM3 selectively channels Dol-P-Man among the four downstream pathways and why muscle/dystroglycan glycosylation is preferentially sensitive remains unresolved.
  • No high-resolution structure of the assembled DPM complex
  • Mechanism of tissue-specific vulnerability undefined
  • Direct CHIP-mediated DPM1 ubiquitination not reconstituted

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-1643685 Disease 2
Partners
DPM1DPM2STUB1
Complex memberships
DPM synthase complex

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Human DPM synthase is a trimeric complex consisting of three subunits: DPM1 (catalytic), DPM2 (regulatory), and DPM3. DPM3 (92 amino acids) associates with DPM1 via its C-terminal domain and with DPM2 via its N-terminal portion. DPM3 directly stabilizes DPM1, while DPM2 stabilizes DPM3. Overexpression of DPM3 in DPM2-null Lec15 cells restored DPM biosynthesis with increased DPM1 levels, demonstrating DPM3 directly stabilizes DPM1 independently of DPM2. DPM2 also plays a role in the enzymatic reaction, as activity was 10-fold higher in its presence. Complementation of DPM2-null Lec15 cells, co-purification, subunit overexpression, functional DPM biosynthesis assay The EMBO journal High 10835346
2005 DPM3 is an essential component of DPM synthase: CHO2.38 cells deficient in DPM3 show no detectable DPM synthase activity and lack GPI-anchored proteins. The coiled-coil domain near the C-terminus of DPM3 is critical for tethering DPM1 to the ER membrane and for enzyme activity. In the absence of DPM3, DPM1 is rapidly degraded by the proteasome; free DPM1 associates strongly with CHIP (C-terminus of Hsc70-interacting protein), a chaperone-dependent E3 ubiquitin ligase, indicating DPM1 is ubiquitinated at least in part by CHIP. The two N-terminal transmembrane regions of DPM3 showed no specific functions. DPM3-deficient CHO2.38 mutant cell line generation, DPM synthase activity assay, GPI-anchor surface staining, domain deletion/mutagenesis, co-immunoprecipitation with CHIP, proteasome inhibitor experiments The Journal of biological chemistry High 16280320
2009 A pathogenic p.L85S missense mutation in the coiled-coil domain of DPM3 reduces its binding capacity for catalytic DPM1, leading to reduced DPM synthase activity. This reduces Dol-P-Man availability for all four Dol-P-Man-dependent glycosylation pathways in the ER, with the most prominent effect being strongly reduced O-mannosylation of alpha-dystroglycan in muscle, explaining the muscular dystrophy phenotype. Complementation of DPM3-deficient CHO2.38 cells confirmed pathogenicity. Sanger sequencing, CHO2.38 cell complementation, cotransfection binding assay (DPM3 L85S vs DPM1), DPM synthase activity assay, muscle biopsy O-mannosylation analysis by immunohistochemistry American journal of human genetics High 19576565
2013 A p.Gly152Val mutation in DPM1 reduces its binding to DPM3 (an essential non-catalytic subunit of the DPM complex), demonstrated by reduced co-immunoprecipitation of mutant DPM1 with DPM3 in transfected cells. DPM1 activity in patient fibroblasts was reduced by 80% without reduced substrate affinity, suggesting a decrease in amount of active enzyme rather than catalytic impairment. Fibroblast DPM1 enzymatic activity assay with substrate affinity measurement, transfection with tagged wild-type and mutant DPM1 followed by co-immunoprecipitation with DPM3 Molecular genetics and metabolism Medium 23856421
2019 In DPM3-CDG patients presenting with muscle dystrophy, both O-mannosylation of alpha-dystroglycan (αDG) and N-glycosylation of beta-dystroglycan (βDG) in skeletal muscle are affected — specifically, a consistent lack of one N-glycan on βDG was detected by western blot. This indicates that defects in DPM3 impair both O-glycosylation of αDG and N-glycosylation of βDG in skeletal muscle, suggesting these are tissue-specific readouts of DPM synthesis pathway deficiency. Skeletal muscle biopsy analysis, western blot of βDG N-glycosylation, immunostaining of αDG O-mannosylation in three DPM3-CDG patients Journal of inherited metabolic disease Medium 30931530
2017 A homozygous c.131T>G (p.Leu44Pro) substitution in DPM3 leads to a 50% reduction in DPM synthase enzymatic activity, and decreased availability of Dol-P-Man as the essential mannose donor substrate for POMT1/2 explains defective skeletal muscle alpha-dystroglycan O-glycosylation, causing limb girdle muscular dystrophy. Exome sequencing, DPM synthase activity measurement in patient cells, muscle biopsy alpha-dystroglycan glycosylation analysis Neuromuscular disorders : NMD Medium 28803818
2016 Antisense morpholino-mediated depletion of dpm3 in zebrafish results in muscle disorganization, low DPM synthase complex activity, increased apoptotic nuclei, and hypoglycosylation of alpha-dystroglycan in muscle fibers, establishing a direct role for DPM3 in stabilizing muscle structure and DPM complex function in vivo. Antisense morpholino knockdown in zebrafish, DPM synthase activity assay, immunostaining for alpha-dystroglycan glycosylation, apoptosis detection in muscle Biochemical and biophysical research communications Medium 27291147
2001 DPM3/prostin-1 expression is regulated by phospholipase C-gamma (PLCγ) signaling — pharmacological inhibition of PLCγ with U73122 induces prostin-1/DPM3 expression in PLCγ-competent prostate cancer cells. Exogenous overexpression of DPM3 in COS cells leads to apoptosis. Microarray expression analysis, pharmacological PLCγ inhibition (U73122), exogenous DPM3 overexpression in COS cells with apoptosis readout Oncogene Low 11420690

Source papers

Stage 0 corpus · 36 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Deficiency of Dol-P-Man synthase subunit DPM3 bridges the congenital disorders of glycosylation with the dystroglycanopathies. American journal of human genetics 153 19576565
2009 Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides. Human mutation 135 19862844
2000 Human dolichol-phosphate-mannose synthase consists of three subunits, DPM1, DPM2 and DPM3. The EMBO journal 117 10835346
2012 DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy. Annals of neurology 112 23109149
2013 Congenital disorder of glycosylation due to DPM1 mutations presenting with dystroglycanopathy-type congenital muscular dystrophy. Molecular genetics and metabolism 62 23856421
2005 DPM1, the catalytic subunit of dolichol-phosphate mannose synthase, is tethered to and stabilized on the endoplasmic reticulum membrane by DPM3. The Journal of biological chemistry 44 16280320
2018 Detection of variants in dystroglycanopathy-associated genes through the application of targeted whole-exome sequencing analysis to a large cohort of patients with unexplained limb-girdle muscle weakness. Skeletal muscle 40 30060766
2004 Congenital disorder of glycosylation (CDG) type Ie. A new patient. Journal of inherited metabolic disease 40 15669674
2002 In vivo interaction between the polyprenol phosphate mannose synthase Ppm1 and the integral membrane protein Ppm2 from Mycobacterium smegmatis revealed by a bacterial two-hybrid system. The Journal of biological chemistry 36 12427759
2021 Genetic variations and clinical spectrum of dystroglycanopathy in a large cohort of Chinese patients. Clinical genetics 31 33200426
2015 Dystroglycanopathies: About Numerous Genes Involved in Glycosylation of One Single Glycoprotein. Journal of neuromuscular diseases 26 28198708
2006 A new intronic mutation in the DPM1 gene is associated with a milder form of CDG Ie in two French siblings. Pediatric research 24 16641202
2001 Dolichol-phosphate-mannose-3 (DPM3)/prostin-1 is a novel phospholipase C-gamma regulated gene negatively associated with prostate tumor invasion. Oncogene 24 11420690
2023 Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review. International journal of molecular sciences 21 37239976
2022 Synergistic use of glycomics and single-molecule molecular inversion probes for identification of congenital disorders of glycosylation type-1. Journal of inherited metabolic disease 19 35279850
2012 Novel POMGNT1 point mutations and intragenic rearrangements associated with muscle-eye-brain disease. Journal of the neurological sciences 18 22554691
2016 Dolichol-phosphate mannose synthase depletion in zebrafish leads to dystrophic muscle with hypoglycosylated α-dystroglycan. Biochemical and biophysical research communications 17 27291147
2023 Fecal microbiota transplantation alleviates experimental colitis through the Toll-like receptor 4 signaling pathway. World journal of gastroenterology 16 37662857
2015 Dolichol phosphate mannose synthase from the pathogenic yeast Candida albicans is a multimeric enzyme. Biochimica et biophysica acta 16 26299246
2019 A mutation in mannose-phosphate-dolichol utilization defect 1 reveals clinical symptoms of congenital disorders of glycosylation type I and dystroglycanopathy. JIMD reports 14 31741824
1984 Response of pulmonary cellular defenses to the inhalation of high concentrations of diesel exhaust. Journal of toxicology and environmental health 14 6208373
2011 Intragenic rearrangements in LARGE and POMGNT1 genes in severe dystroglycanopathies. Neuromuscular disorders : NMD 12 21727005
2019 Dilated cardiomyopathy and limb-girdle muscular dystrophy-dystroglycanopathy due to novel pathogenic variants in the DPM3 gene. Neuromuscular disorders : NMD 11 31266720
2017 A homozygous DPM3 mutation in a patient with alpha-dystroglycan-related limb girdle muscular dystrophy. Neuromuscular disorders : NMD 11 28803818
2019 Toward understanding tissue-specific symptoms in dolichol-phosphate-mannose synthesis disorders; insight from DPM3-CDG. Journal of inherited metabolic disease 8 30931530
2017 Microdeletion of chromosome 1q21.3 in fraternal twins is associated with mental retardation, microcephaly, and epilepsy. Intractable & rare diseases research 8 28357185
2022 A recurrent homozygous missense DPM3 variant leads to muscle and brain disease. Clinical genetics 7 35932216
2003 A single point mutation resulting in an adversely reduced expression of DPM2 in the Lec15.1 cells. Biochemical and biophysical research communications 7 14680801
1991 Acquisition of thymidylate by the obligate intracytoplasmic bacterium Rickettsia prowazekii. Journal of bacteriology 7 1900279
2011 Cloning and functional analysis of the dpm2 and dpm3 genes from Trichoderma reesei expressed in a Saccharomyces cerevisiae dpm1Δ mutant strain. Biological chemistry 5 21521073
2020 Yil102c-A is a Functional Homologue of the DPMII Subunit of Dolichyl Phosphate Mannose Synthase in Saccharomyces cerevisiae. International journal of molecular sciences 4 33255655
2003 The divergent 5' ends of DPM2 mRNAs originate from the alternative splicing of two adjacent introns: characterization of the hamster DPM2 gene. Biochemical and biophysical research communications 2 14680839
1999 First Report on Pathogenic Variability of Different Isolates of Diaporthe phaseolorum var. meridionalis on Soybean in Argentina. Plant disease 2 30841283
2025 Selenium Supplementation Mitigates Copper-Induced Systemic Toxicity via Transcriptomic Reprogramming and Redox Homeostasis in Mice. Foods (Basel, Switzerland) 1 41154064
2026 Single-cell RNA and DNA methylome profiling reveal liquid helium vitrification enhances porcine parthenogenetically activated blastocyst viability. BMC genomics 0 41928102
2025 Clinical and genetic characterization of congenital disorders of glycosylation in 20 Chinese patients. Orphanet journal of rare diseases 0 41437099

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