Affinage

LEMD3

Inner nuclear membrane protein Man1 · UniProt Q9Y2U8

Length
911 aa
Mass
100.0 kDa
Annotated
2026-06-10
56 papers in source corpus 24 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LEMD3/MAN1 is an integral inner nuclear membrane (INM) protein that serves as a membrane-tethered antagonist of TGF-β/BMP/activin signaling and as an organizer of peripheral heterochromatin (PMID:10671519, PMID:15489854, PMID:41044070). It is anchored at the INM through its N-terminal nucleoplasmic LEM-domain region, which is necessary and sufficient for INM retention and binds directly to BAF, lamin A, lamin B1, and emerin, retaining MAN1 by a diffusion-retention mechanism (PMID:11896184, PMID:12684533, PMID:15681850). Its C-terminal nucleoplasmic tail folds into a winged-helix domain coupled to a U2AF homology motif (UHM) domain; an intramolecular UHM-ULM interaction creates the surface that directly engages the MH2 domain of receptor-activated Smads (Smad1/2/3) but not Smad4, the structural basis by which MAN1 discriminates R-Smads from the common mediator (PMID:16648637, PMID:20715792, PMID:30321401). By sequestering R-Smads at the nuclear envelope, MAN1 blocks their phosphorylation, heterodimerization with Smad4, and nuclear accumulation, and competes with the transcription factor FAST1 for Smad2, thereby repressing TGF-β/BMP/activin-responsive transcription (PMID:15647271, PMID:23779087). MAN1 promotes R-Smad dephosphorylation through direct association with phosphatase activity, binding PPM1A in vitro and assembling the CTDNEP1-NEP1R1 phosphatase complex at the INM via a binding site independent of its R-Smad site (PMID:23779087). Loss-of-function studies across mouse, Drosophila, and C. elegans establish that MAN1 restrains Smad signaling in vivo: Man1-deficient mouse embryos die from vascular remodeling and yolk-sac vascularization defects with elevated phospho-Smad2/3, exhibit left-right axis defects via node-independent Nodal regulation, and Drosophila mutants show expanded phospho-Mad and BMP-dependent wing and synaptic phenotypes (PMID:16943282, PMID:17329363, PMID:18697220, PMID:20036230, PMID:27848060). MAN1 also anchors H3K9me2/3-marked heterochromatin at the nuclear periphery through CBX3, maintaining 3D chromatin architecture and contractile gene expression in vascular smooth muscle cells (PMID:41044070). Heterozygous loss-of-function mutations in LEMD3 cause osteopoikilosis, Buschke-Ollendorff syndrome, and melorheostosis (PMID:15489854). Beyond these themes, MAN1 has additional reported roles in circadian transcription and mitotic regulation, including direct binding to clock gene promoters and cell-cycle phosphorylation that suppresses BAF binding (PMID:19166343, PMID:25182847).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2000 High

    Established LEMD3/MAN1 as a distinct LEM-domain inner nuclear membrane protein, defining its membrane topology and family membership before any function was known.

    Evidence Biochemical extraction, transfection/immunofluorescence, and sequence analysis identifying two TM segments, an N-terminal LEM domain, and a C-terminal nucleoplasmic tail

    PMID:10671519

    Open questions at the time
    • No binding partners identified
    • No functional role established
  2. 2002 High

    Defined how MAN1 is retained at the INM, showing the nucleoplasmic N-terminus is necessary and sufficient and that retention depends on binding an immobile nuclear component.

    Evidence Truncation-mutant immunofluorescence and FRAP of GFP-MAN1 in transfected cells

    PMID:11896184

    Open questions at the time
    • Identity of the retained-on nuclear binding partner not defined in this study
  3. 2003 High

    Identified the nuclear envelope anchoring partners and an essential mitotic function by showing MAN1 binds lamin and BAF and shares roles with emerin in chromosome segregation.

    Evidence In vitro direct binding assays and RNAi epistasis in C. elegans with mitotic immunostaining

    PMID:12684533

    Open questions at the time
    • Mechanism of mitotic chromatin bridging not resolved
    • Conservation to human function inferred from ortholog
  4. 2004 High

    Connected LEMD3 to human disease and to TGF-β/BMP signaling, identifying it as a Smad-interacting antagonist of both pathways and the gene mutated in sclerosing bone dysplasias.

    Evidence Linkage analysis and mutation identification in patients, cell-based BMP/TGF-β reporters, co-immunoprecipitation; yeast two-hybrid, GST pull-down, and reporter/proliferation assays mapping the C-terminal Smad2/3 interface

    PMID:15489854 PMID:15601644

    Open questions at the time
    • Mechanism of Smad inhibition not yet defined
    • Structural basis of R-Smad selectivity unknown
  5. 2005 High

    Resolved the mechanism of Smad repression and the bipartite domain organization, showing MAN1 sequesters R-Smads (not Smad4) at the INM to block phosphorylation, heterodimerization, and nuclear translocation, while the N-terminus binds lamins/BAF/emerin.

    Evidence Co-IP, domain mapping, point mutagenesis, phosphorylation and reporter assays; blot overlay and co-IP defining N- and C-terminal partner binding

    PMID:15647271 PMID:15681850

    Open questions at the time
    • How MAN1 promotes loss of R-Smad phosphorylation not established
    • Some C-terminal BAF binding later reinterpreted as DNA-mediated
  6. 2006 High

    Provided the first structural insight and demonstrated the in vivo developmental requirement, showing the C-terminus is a DNA-binding winged-helix domain and that Man1 loss causes embryonic vascular defects with hyperactive Smad2/3.

    Evidence NMR structure with DNA-binding assays; conditional knockout mouse embryo phenotyping with in situ hybridization and immunostaining

    PMID:16648637 PMID:16943282

    Open questions at the time
    • Functional role of DNA binding in vivo unclear
    • Direct phosphatase mechanism not yet identified
  7. 2007 High

    Confirmed the vascular/Smad phenotype with an independent allele and tetraploid rescue, localizing the lethality to yolk-sac vascularization and elevated ALK5-driven SMAD2/3 activity.

    Evidence Gene-trap mouse, tetraploid rescue, ES-cell differentiation, phospho-Smad immunostaining and reporters

    PMID:17329363

    Open questions at the time
    • Tissue-autonomous versus systemic contributions not fully separated
  8. 2008 Medium

    Extended the Smad-antagonist role to additional in vivo contexts, demonstrating conserved Drosophila BMP/TGF-β antagonism and a node-independent role in regulating Nodal/Smad-driven left-right asymmetry.

    Evidence Drosophila yeast two-hybrid and null-allele phenotyping with phospho-Smad staining; mouse genetic epistasis with Nodal hypomorphs and laterality marker in situ hybridization

    PMID:18697220 PMID:18723885

    Open questions at the time
    • Direct biochemical mechanism of Nodal regulation not addressed
    • Single-lab genetic interactions
  9. 2009 High

    Identified cell-cycle regulation of MAN1 and refined its BMP-antagonist function, mapping mitotic phosphosites that suppress BAF binding and showing domain-specific BMP antagonism at the synapse and wing crossvein.

    Evidence Xenopus egg cell-free phosphosite mapping by MS/MS with phosphomimetic BAF-binding assays; Drosophila MAN1ΔC mutagenesis with phospho-Mad staining, electrophysiology, and genetic interaction

    PMID:19166343 PMID:20036230

    Open questions at the time
    • Kinases responsible for mitotic phosphorylation not identified
    • In vivo consequence of phospho-regulation untested
  10. 2010 High

    Elucidated the molecular architecture of Smad binding, showing an intramolecular UHM-ULM interaction within the C-terminal region is required for Smad2 engagement.

    Evidence NMR, SAXS, GST pull-down, fluorescence binding, and yeast two-hybrid mapping of the linker-UHM-C-terminus interface

    PMID:20715792

    Open questions at the time
    • Atomic detail of the MAN1-R-Smad contact not yet resolved
  11. 2011 Medium

    Corrected the interaction map by showing the reported C-terminal MAN1-BAF interaction is DNA-mediated rather than a direct protein-protein contact.

    Evidence In vitro binding assays under DNA-free conditions

    PMID:21966431

    Open questions at the time
    • Biological role, if any, of the DNA-bridged association not defined
    • Single-lab negative result
  12. 2013 High

    Built a 3D model of the MAN1-Smad2 complex and linked MAN1 to active dephosphorylation, showing it competes with FAST1 for Smad2 and binds the phosphatase PPM1A.

    Evidence NMR/SAXS modeling, co-IP, in vitro competition and direct MAN1-PPM1A binding, phospho-Smad western blotting

    PMID:23779087

    Open questions at the time
    • Whether PPM1A is the principal physiological R-Smad phosphatase at the INM unresolved
    • In-cell selectivity for R-Smad over Smad4 complexes differs from in vitro
  13. 2014 Medium

    Linked the INM protein to transcriptional regulation of the circadian clock, showing MAN1 directly binds the BMAL1 promoter and modulates its expression.

    Evidence ChIP, transcriptional reporters, knockdown/overexpression with BMAL1 readout

    PMID:25182847

    Open questions at the time
    • Mechanism connecting membrane localization to promoter binding unclear
    • Single-lab finding
  14. 2016 Medium

    Reinforced the synaptic BMP-antagonist role, showing MAN1 loss causes BMP-dependent synaptic overgrowth and that MAN1 limits BMP component accumulation at synapses.

    Evidence Drosophila genetics, BMP pathway double mutants, EM of synapse ultrastructure, immunostaining

    PMID:27848060

    Open questions at the time
    • Molecular mechanism of synaptic BMP component regulation not defined
  15. 2017 Medium

    Demonstrated a cell-fate consequence of MAN1 Smad regulation, showing knockdown shifts mesenchymal stem cells toward osteogenesis with increased nuclear Smad and β-Catenin.

    Evidence siRNA knockdown/overexpression in MSCs with differentiation assays and nuclear marker immunostaining

    PMID:28449239

    Open questions at the time
    • Direct versus indirect role in β-Catenin regulation not established
    • Single-lab, single method set
  16. 2018 High

    Defined the atomic basis of R-Smad recognition, showing the UHM-ULM-generated hydrophobic surface contacts conserved MH2 elements to distinguish R-Smads from Smad4.

    Evidence X-ray crystallography of SMAD2-MAN1 and SMAD1-MAN1 complexes

    PMID:30321401

    Open questions at the time
    • Structural context within the full-length INM-anchored protein not captured
  17. 2019 Medium

    Confirmed a conserved circadian function in vivo, showing MAN1 knockdown in pacemaker neurons lengthens period by targeting period (per) transcription.

    Evidence Neuron-specific RNAi, RT-PCR, western blot, per genetic epistasis, locomotor behavior

    PMID:31230212

    Open questions at the time
    • Direct promoter binding to per not shown
    • Relationship to mammalian BMAL1 regulation unclear
  18. 2020 Medium

    Mapped the MAN1 proximity interactome and distinguished it from other LEM proteins, identifying enrichment for ribonucleoprotein assembly components and ruling out a role in nucleotide excision repair.

    Evidence Comparative BioID mass spectrometry, UV-C survival, γH2AX immunostaining

    PMID:32085595

    Open questions at the time
    • Functional role in RNP assembly only suggestive
    • No validated RNP partner characterized
  19. 2025 High

    Established a chromatin-organizing function, showing LEMD3 anchors H3K9me2/3 heterochromatin at the nuclear periphery via CBX3 to maintain 3D genome architecture and the VSMC contractile phenotype.

    Evidence CRISPR screen, Co-IP/MS, Hi-C, ATAC-seq, RNA-seq, and conditional knockout mice

    PMID:41044070

    Open questions at the time
    • How CBX3 tethering integrates with Smad-antagonist function unresolved
    • Generalizability beyond VSMCs untested
  20. 2024 Medium

    Identified the long-sought R-Smad phosphatase recruited by MAN1, showing it assembles CTDNEP1-NEP1R1 at the INM via a binding site separate from its R-Smad site to drive R-Smad dephosphorylation.

    Evidence Domain mapping, mutagenesis, structural prediction, phospho-Smad and complex-disruption assays (preprint)

    Open questions at the time
    • Not yet peer-reviewed
    • Relationship to earlier PPM1A finding not reconciled
    • No structure of the assembled INM complex

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MAN1's two principal activities—membrane-tethered R-Smad termination and CBX3-mediated heterochromatin anchoring—are coordinated, and how each contributes to the distinct LEMD3 disease phenotypes, remains unresolved.
  • No integrated model linking Smad and chromatin functions
  • Tissue-specific basis of osteopoikilosis/melorheostosis not mechanistically explained
  • Phosphatase identity (PPM1A vs CTDNEP1-NEP1R1) not reconciled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 2 GO:0140110 transcription regulator activity 2 GO:0003677 DNA binding 1 GO:0042393 histone binding 1
Localization
GO:0005635 nuclear envelope 3 GO:0005634 nucleus 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-9909396 Circadian clock 2 R-HSA-4839726 Chromatin organization 1
Partners
BAF/BANF1CBX3EMDLMNAPPM1ASMAD1SMAD2SMAD3
Complex memberships
CTDNEP1-NEP1R1 phosphatase complex (INM)

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 MAN1 (LEMD3) is an integral inner nuclear membrane protein with two hydrophobic transmembrane segments, an N-terminal LEM domain (~40 aa shared with LAP2 and emerin), and a C-terminal nucleoplasmic tail. When expressed in transfected cells it is exclusively targeted to the nuclear envelope, consistent with inner nuclear membrane localization. Cell extraction (integral membrane protein), transfection/confocal immunofluorescence, protein sequence analysis The Journal of biological chemistry High 10671519
2002 The nucleoplasmic N-terminal domain of MAN1 is necessary and sufficient for inner nuclear membrane retention; the transmembrane segments with the C-terminal domain alone are not targeted to the INM. FRAP of GFP-MAN1 shows the fusion protein is relatively immobile in the nuclear envelope compared to the ER, consistent with binding to a nuclear component (diffusion-retention model). Confocal immunofluorescence of truncation mutants expressed in transfected cells; FRAP Journal of cell science High 11896184
2003 C. elegans Ce-MAN1 binds directly to Ce-lamin and Ce-BAF in vitro, and requires Ce-lamin for its nuclear envelope localization. Ce-MAN1 has overlapping essential functions with Ce-emerin: combined RNAi depletion of both causes lethal anaphase chromosome bridging and cytokinesis failure (cut phenotype) with retention of phospho-histone H3 on bridged chromatin and failure to recruit lamin or BAF. In vitro direct binding assays, RNAi epistasis in C. elegans, immunostaining of mitotic cells Proceedings of the National Academy of Sciences of the United States of America High 12684533
2004 LEMD3/MAN1 is mutated (heterozygous loss-of-function) in osteopoikilosis, Buschke-Ollendorff syndrome, and melorheostosis. LEMD3 interacts with BMP and activin/TGF-β receptor-activated Smads and antagonizes both signaling pathways in human cells. Genome-wide linkage analysis, mutation identification in patients, cell-based reporter assays for BMP/TGF-β signaling, protein interaction (co-immunoprecipitation) Nature genetics High 15489854
2004 The C-terminal nucleoplasmic domain of human MAN1 directly binds Smad2 and Smad3 (but not the N-terminal domain) via yeast two-hybrid and GST pull-down under stringent conditions; antibodies against MAN1 co-immunoprecipitate Smad2 from cells. Overexpression of MAN1 or its C-terminal domain inhibits TGF-β-induced transcriptional reporter activation and TGF-β-induced cell proliferation arrest. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, transcriptional reporter assays, stable cell line overexpression with proliferation assay Human molecular genetics High 15601644
2005 MAN1 associates with R-Smads (but not Smad4) at the inner nuclear membrane via its RNA recognition motif (RRM) domain in a ligand-independent manner. Overexpression of MAN1 inhibits R-Smad phosphorylation, heterodimerization with Smad4, and nuclear translocation, repressing TGF-β, BMP2, and activin-responsive promoters. A point mutation disrupting MAN1-Smad interaction abolishes transcriptional repression. Co-immunoprecipitation, reporter gene assays, phosphorylation assays, domain mapping, point mutagenesis The Journal of biological chemistry High 15647271
2005 The N-terminal domain of MAN1 (MAN1-N, containing the LEM domain) binds directly to BAF, lamin A, lamin B1, and directly to emerin in blot overlay and co-immunoprecipitation assays. The C-terminal domain (MAN1-C) binds the transcription regulators GCL, Btf, and BAF through a non-LEM BAF-binding motif (Ser-Arg-Val sequence). Blot overlay assays, co-immunoprecipitation, sequence alignment identifying conserved BAF-binding motif The Journal of biological chemistry Medium 15681850
2006 The C-terminal nucleoplasmic region of MAN1 adopts a winged helix domain fold (determined by NMR) that binds DNA through its positively charged recognition helix H3. Structural modeling indicates that DNA-binding and R-Smad-binding surfaces are largely distinct, suggesting simultaneous binding to both DNA and R-Smads is possible. NMR structural characterization, DNA binding assays The Journal of biological chemistry High 16648637
2006 Man1-deficient mouse embryos (lacking the Smad-interacting domain) die at mid-gestation due to defects in vascular remodeling. The primary capillary plexus forms but remodeling is perturbed, correlated with upregulated Tgfb1 expression, abnormally activated Smad2/3 signaling, increased extracellular matrix deposition, and disturbed mural cell recruitment. Conditional knockout mouse model, in situ hybridization, immunostaining, embryo phenotyping Development (Cambridge, England) High 16943282
2007 MAN1 gene-trap homozygous (Man1GT/GT) mouse embryos die by E10.5 due to abnormal yolk-sac vascularization. MAN1GT/GT embryonic stem cells and their derivatives show increased phosphorylation and nuclear localization of SMAD2/3 and elevated SMAD transcriptional activity, predominantly from the ALK5 pathway. Gene-trap mouse model, tetraploid rescue experiments, embryonic stem cell differentiation, phospho-Smad immunostaining, transcriptional reporter assays Development (Cambridge, England) High 17329363
2008 Drosophila MAN1 (dMAN1) associates with receptor-regulated Smads (Mad), lamins, and the LEM-domain protein Bocksbeutel by yeast two-hybrid. Null dMAN1 mutants show decreased viability, male sterility, wing patterning defects, and increased phospho-Smad staining in wing discs, consistent with a role in TGF-β/BMP signaling in vivo. Yeast two-hybrid, P-element-generated null alleles, immunostaining of wing discs, genetic phenotype analysis Genetics Medium 18723885
2008 Man1-deficient mouse embryos exhibit bilateral expression of Nodal, Lefty2, and Pitx2 in the lateral plate mesoderm (left-right axis defects), with normal midline Lefty1. Genetic crosses with Nodal hypomorphs show that bilateral Nodal expression in Man1-deficient embryos is node-independent, indicating Man1 regulates left-right asymmetry by controlling Nodal/Smad signaling outside the node. Mouse genetic epistasis (double mutant Man1Δ/Δ; Nodalneo/neo), in situ hybridization of laterality markers Developmental dynamics Medium 18697220
2009 MAN1 is phosphorylated in a cell cycle-dependent manner in the Xenopus egg cell-free system. M-phase-specific phosphorylation sites Thr-209, Ser-351, and Ser-402 were identified by MS/MS. Phosphorylation at Ser-402 (tested by S402A and S402E mutants) suppresses MAN1 binding to BAF during mitosis. Xenopus egg cell-free system, Titansphere column chromatography, MS/MS sequencing, in vitro BAF binding assay with phosphomimetic mutants Biochemistry High 19166343
2009 Drosophila MAN1 (MAN1ΔC mutants lacking the C-terminal RRM/Mad-binding domain) show wing crossvein patterning defects with expanded phospho-Mad accumulation and ectopic cv-2 expression in pupal wings, and a presynaptic role at the neuromuscular junction. MAN1 overexpression in wing discs inhibits crossvein development and BMP signaling. Genetic interaction experiments confirm MAN1 is a BMP signaling antagonist at the NMJ and during CV formation. Targeted mutagenesis (MAN1ΔC), immunostaining for phospho-Mad, in situ hybridization, electrophysiology, genetic interaction Developmental biology High 20036230
2010 The C-terminal region of MAN1 that binds Smad2 comprises a winged helix domain, a linker, a U2AF homology motif (UHM) domain, and a disordered C-terminus. The linker acts as an intramolecular UHM ligand motif (ULM) interacting with the UHM domain; this intramolecular UHM-ULM interaction is critical for Smad2 binding (micromolar affinity). Mapping by GST pull-down, fluorescence, and yeast two-hybrid defined the linker, UHM domain, and C-terminus as the Smad2 binding interface. NMR spectroscopy, small-angle X-ray scattering (SAXS), GST pull-down, fluorescence binding assay, yeast two-hybrid Biochemistry High 20715792
2011 BAF does not directly interact with MAN1-C in the absence of DNA; the previously reported interaction is an indirect association mediated by DNA binding and is not biologically relevant as a direct protein-protein interaction. In vitro binding assays under DNA-free conditions PloS one Medium 21966431
2013 3D structure of the MAN1 C-terminal region bound to Smad2 was modeled from NMR and SAXS data. MAN1 competes with the transcription factor FAST1 for Smad2 binding in vitro and in cells. MAN1 can bind activated Smad2-Smad4 and Smad3-Smad4 complexes in vitro but in cells binds only Smad2/3 not Smad4-containing complexes. MAN1 overexpression leads to Smad2/3 dephosphorylation; MAN1 binds directly in vitro to the phosphatase PPM1A, which dephosphorylates Smad2/3. NMR, SAXS, co-immunoprecipitation, in vitro competition assays, in vitro direct binding (MAN1-PPM1A), phospho-Smad western blotting Science signaling High 23779087
2014 MAN1 directly binds the BMAL1 promoter and positively modulates BMAL1 transcription, establishing a connection between the inner nuclear membrane and circadian clock regulation. Chromatin immunoprecipitation (ChIP), transcriptional reporter assays, MAN1 knockdown/overexpression with BMAL1 expression readout eLife Medium 25182847
2016 In Drosophila, loss of MAN1 causes synaptic overgrowth at neuromuscular junctions sensitive to BMP signaling levels; genetic removal of key BMP components attenuates BMP-induced synaptic overgrowth in MAN1 mutants. MAN1 negatively regulates accumulation and distribution of BMP signaling components at synapses. Drosophila genetics (null mutants, BMP pathway double mutants), electron microscopy of synapse ultrastructure, immunostaining Cellular and molecular neurobiology Medium 27848060
2017 MAN1 knockdown in mesenchymal stem cells (MSCs) increases osteogenesis and mineralization and decreases adipogenesis, associated with increased nuclear accumulation of regulatory Smads and Smad-related complexes and elevated nuclear β-Catenin. MAN1 overexpression primarily decreases adipogenesis without affecting osteogenesis. siRNA knockdown and overexpression in MSCs, osteogenic/adipogenic differentiation assays, immunostaining for nuclear Smad and β-Catenin Journal of cellular biochemistry Medium 28449239
2018 Crystal structures of SMAD2-MAN1 and SMAD1-MAN1 complexes show that the intramolecular UHM-ULM interaction of MAN1 creates a hydrophobic surface that contacts the H2 helix, β8/β9 strands, and L3 loop of the MH2 domain of R-SMAD proteins. This surface is the conserved mechanism by which SMAD cofactors distinguish R-SMADs from Smad4. X-ray crystallography of SMAD2-MAN1 and SMAD1-MAN1 complexes Nucleic acids research High 30321401
2019 MAN1 knockdown in Drosophila pacemaker neurons lengthens locomotor rhythm period; molecular analysis shows reduced mRNA and protein levels of core clock gene period (per). Overexpression of per rescues the long-period phenotype, and per mutation is epistatic to MAN1 knockdown, indicating MAN1 sets circadian pace by targeting per transcription. Neuron-specific RNAi knockdown in Drosophila, RT-PCR, western blotting, genetic epistasis (per mutant × MAN1 RNAi), behavioral (locomotor) assay Neuroscience bulletin Medium 31230212
2020 Proximity biotinylation-based comparative interactome analysis of MAN1 identifies interactors enriched for ribonucleoprotein complex assembly components, suggesting a role for MAN1 in RNP complex assembly. MAN1 depletion (unlike LEM2 depletion) does not impair nucleotide excision repair. BioID proximity biotinylation mass spectrometry (comparative with emerin and LEM2), UV-C irradiation survival assay, γH2AX immunostaining Cells Medium 32085595
2025 LEMD3 interacts with CBX3 (a reader of H3K9me2/3) to anchor heterochromatin at the nuclear periphery in vascular smooth muscle cells (VSMCs). Lemd3 deficiency disrupts 3D chromatin architecture (increased inter-TAD interactions at A/B compartment boundaries), decreases chromatin accessibility, and represses VSMC contractile gene expression, causing loss of the contractile phenotype and exacerbated intimal hyperplasia in mice. Genome-scale CRISPR screen, protein interactome analysis (Co-IP/MS), Hi-C (3D chromatin), ATAC-seq, RNA-seq, Lemd3 conditional knockout in mice Nature communications High 41044070
2024 MAN1 forms an inner nuclear membrane complex with the CTDNEP1-NEP1R1 phosphatase to mediate R-SMAD dephosphorylation and inactivation. Structural prediction, domain mapping, and mutagenesis show MAN1 has independent binding sites for CTDNEP1-NEP1R1 and R-SMADs. Disruption of this complex leads to nuclear accumulation of active R-SMADs and aberrant TGF-β signaling even without ligand. CTDNEP1-NEP1R1 is identified as the elusive R-SMAD phosphatase. Protein-protein interaction (domain mapping, mutagenesis), structural prediction, phospho-Smad assays, complex disruption experiments bioRxivpreprint Medium

Source papers

Stage 0 corpus · 56 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. Nature genetics 326 15489854
2000 MAN1, an inner nuclear membrane protein that shares the LEM domain with lamina-associated polypeptide 2 and emerin. The Journal of biological chemistry 300 10671519
2003 MAN1 and emerin have overlapping function(s) essential for chromosome segregation and cell division in Caenorhabditis elegans. Proceedings of the National Academy of Sciences of the United States of America 178 12684533
2004 MAN1, an integral protein of the inner nuclear membrane, binds Smad2 and Smad3 and antagonizes transforming growth factor-beta signaling. Human molecular genetics 171 15601644
2005 The integral inner nuclear membrane protein MAN1 physically interacts with the R-Smad proteins to repress signaling by the transforming growth factor-{beta} superfamily of cytokines. The Journal of biological chemistry 150 15647271
2000 C. elegans nuclear envelope proteins emerin, MAN1, lamin, and nucleoporins reveal unique timing of nuclear envelope breakdown during mitosis. Molecular biology of the cell 149 10982402
2005 LEM2 is a novel MAN1-related inner nuclear membrane protein associated with A-type lamins. Journal of cell science 126 16339967
2005 Direct binding of nuclear membrane protein MAN1 to emerin in vitro and two modes of binding to barrier-to-autointegration factor. The Journal of biological chemistry 108 15681850
2012 Fission yeast Lem2 and Man1 perform fundamental functions of the animal cell nuclear lamina. Nucleus (Austin, Tex.) 87 22540024
2001 Identification and characterization of the Cryptococcus neoformans phosphomannose isomerase-encoding gene, MAN1, and its impact on pathogenicity. Molecular microbiology 76 11359567
2002 Intracellular trafficking of MAN1, an integral protein of the nuclear envelope inner membrane. Journal of cell science 71 11896184
2007 Deactivating germline mutations in LEMD3 cause osteopoikilosis and Buschke-Ollendorff syndrome, but not sporadic melorheostosis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 60 17087626
2006 Germline LEMD3 mutations are rare in sporadic patients with isolated melorheostosis. Human mutation 54 16470551
2006 The carboxyl-terminal nucleoplasmic region of MAN1 exhibits a DNA binding winged helix domain. The Journal of biological chemistry 54 16648637
2006 Man1, an inner nuclear membrane protein, regulates vascular remodeling by modulating transforming growth factor beta signaling. Development (Cambridge, England) 53 16943282
2007 The nuclear envelope protein MAN1 regulates TGFbeta signaling and vasculogenesis in the embryonic yolk sac. Development (Cambridge, England) 51 17329363
2012 The inner nuclear membrane proteins Man1 and Ima1 link to two different types of chromatin at the nuclear periphery in S. pombe. Nucleus (Austin, Tex.) 48 22156748
2013 Inhibition of TGF-β signaling at the nuclear envelope: characterization of interactions between MAN1, Smad2 and Smad3, and PPM1A. Science signaling 45 23779087
2007 What MAN1 does to the Smads. TGFbeta/BMP signaling and the nuclear envelope. The FEBS journal 42 17489095
2009 Novel and recurrent germline LEMD3 mutations causing Buschke-Ollendorff syndrome and osteopoikilosis but not isolated melorheostosis. Clinical genetics 36 19438932
2001 Expression of the Aspergillus aculeatus endo-beta-1,4-mannanase encoding gene (man1) in Saccharomyces cerevisiae and characterization of the recombinant enzyme. Protein expression and purification 36 11162394
2020 Hsa_circ_0070963 inhibits liver fibrosis via regulation of miR-223-3p and LEMD3. Aging 34 32003753
2008 Tissue-specific defects are caused by loss of the Drosophila MAN1 LEM domain protein. Genetics 34 18723885
2022 The Iron Deficiency-Regulated Small Protein Effector FEP3/IRON MAN1 Modulates Interaction of BRUTUS-LIKE1 With bHLH Subgroup IVc and POPEYE Transcription Factors. Frontiers in plant science 30 35755670
2014 Nuclear envelope protein MAN1 regulates clock through BMAL1. eLife 28 25182847
2010 Structural analysis of the Smad2-MAN1 interaction that regulates transforming growth factor-β signaling at the inner nuclear membrane. Biochemistry 28 20715792
2007 A novel LEMD3 mutation common to patients with osteopoikilosis with and without melorheostosis. Calcified tissue international 28 17622481
2014 Genome-wide scan reveals LEMD3 and WIF1 on SSC5 as the candidates for porcine ear size. PloS one 27 25006967
2005 The Drosophila melanogaster LEM-domain protein MAN1. European journal of cell biology 26 16439308
2010 Buschke-Ollendorff syndrome: absence of LEMD3 mutation in an affected family. Archives of dermatology 24 20083694
2009 The Drosophila LEM-domain protein MAN1 antagonizes BMP signaling at the neuromuscular junction and the wing crossveins. Developmental biology 23 20036230
2018 Structural basis for receptor-regulated SMAD recognition by MAN1. Nucleic acids research 22 30321401
2020 Comparative Interactome Analysis of Emerin, MAN1 and LEM2 Reveals a Unique Role for LEM2 in Nucleotide Excision Repair. Cells 19 32085595
2010 Buschke-Ollendorff syndrome in a three-generation family: influence of a novel LEMD3 mutation to tropoelastin expression. European journal of dermatology : EJD 17 20732851
2021 Heh2/Man1 may be an evolutionarily conserved sensor of NPC assembly state. Molecular biology of the cell 16 34010011
2010 Osteopoikilosis and multiple exostoses caused by novel mutations in LEMD3 and EXT1 genes respectively--coincidence within one family. BMC medical genetics 16 20618940
2008 Man1, an inner nuclear membrane protein, regulates left-right axis formation by controlling nodal signaling in a node-independent manner. Developmental dynamics : an official publication of the American Association of Anatomists 15 18697220
2009 Cell cycle-dependent phosphorylation of MAN1. Biochemistry 14 19166343
2013 Essential roles of LEM-domain protein MAN1 during organogenesis in Xenopus laevis and overlapping functions of emerin. European journal of cell biology 13 24252515
2011 No interaction of barrier-to-autointegration factor (BAF) with HIV-1 MA, cone-rod homeobox (Crx) or MAN1-C in absence of DNA. PloS one 12 21966431
2010 Derivation of Man-1 and Man-2 research grade human embryonic stem cell lines. In vitro cellular & developmental biology. Animal 12 20177994
2010 Buschke-Ollendorff syndrome with striking phenotypic variation resulting from a novel c.2203C>T nonsense mutation in LEMD3. Pediatric dermatology 12 20678097
2019 Nuclear Envelope Protein MAN1 Regulates the Drosophila Circadian Clock via Period. Neuroscience bulletin 10 31230212
2015 Novel Somatic Mutation in LEMD3 Splice Site Results in Buschke-Ollendorff Syndrome with Polyostotic Melorheostosis and Osteopoikilosis. Pediatric dermatology 10 26135202
2016 MAN1 Restricts BMP Signaling During Synaptic Growth in Drosophila. Cellular and molecular neurobiology 8 27848060
2016 Mutation in LEMD3 (Man1) Associated with Osteopoikilosis and Late-Onset Generalized Morphea: A New Buschke-Ollendorf Syndrome Variant. Case reports in dermatological medicine 7 27382493
2015 Identification of a novel LEMD3 Y871X mutation in a three-generation family with osteopoikilosis and review of the literature. Journal of endocrinological investigation 5 26694706
2017 The Role of the Nuclear Envelope Protein MAN1 in Mesenchymal Stem Cell Differentiation. Journal of cellular biochemistry 4 28449239
2020 Osteopoikilosis With Germline LEMD3 Mutation Mimicking Bone Metastases in a Girl With a Concurrent Secreting Mixed Germ Cell Tumor. Journal of pediatric hematology/oncology 2 30951020
2020 Buschke-Ollendorff syndrome with LEMD3 germline stopgain mutation p.R678* presenting as multiple subcutaneous nodules with mucin deposition. Journal of cutaneous pathology 2 32519343
2017 Juvenile elastoma without germline mutations in LEMD3 gene: A case of Buschke-Ollendorff syndrome? Pediatric dermatology 2 29023873
2009 The heterozygous Lemd3 +/GT mouse is not a murine model for osteopoikilosis in humans. Calcified tissue international 2 19862465
2025 The inner nuclear membrane protein LEMD3 organizes the 3D chromatin architecture to maintain vascular smooth muscle cell identity. Nature communications 1 41044070
2019 A novel LEMD3 pathogenic variant in a son and mother with osteopoikilosis. The Turkish journal of pediatrics 1 31990479
2018 Tc-99m MDP Bone SPECT/CT Findings of a Patient Detected with a New Mutation in LEMD3 Gene: A Case of Osteopoikilosis. Molecular imaging and radionuclide therapy 1 29393055
2017 Novel 4-bp Intronic Deletion (c.1560+5_1560+8del) [corrected] in LEMD3 in a Korean Patient With Osteopoikilosis. Annals of laboratory medicine 0 28840995

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