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LCMT1

Leucine carboxyl methyltransferase 1 · UniProt Q9UIC8

Length
334 aa
Mass
38.4 kDa
Annotated
2026-06-10
16 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LCMT1 is the principal leucine carboxyl methyltransferase that activates the PP2A subfamily of protein phosphatases by methylating the conserved C-terminal leucine (Leu-309) of their catalytic subunits, thereby directing assembly of substrate-specific holoenzymes (PMID:21292165, PMID:23840384). Crystal structures of LCMT1 alone and bound to PP2A show that its active-site pocket engages the PP2A C-terminus while the activated PP2A active site reciprocally stimulates methylation, defining a feed-forward mechanism that converts catalytically active PP2A into B-subunit-containing holoenzymes (PMID:21292165). Beyond PP2A, LCMT1 is the major carboxyl methyltransferase for the PP4 and PP6 catalytic subunits, and its loss selectively disrupts regulatory-subunit assembly (most dramatically the PP4R1-PP4 complex) and reduces steady-state levels of B-type and PP4R1 regulatory subunits, with downstream hyperphosphorylation of substrates such as HDAC3 (PMID:27507813). Methylation-dependent recruitment of specific B subunits channels PP2A toward defined outputs: a LCMT1→methyl-PP2A→Bα axis drives F-actin reorganization and neurite outgrowth and partitions PP2A and Tau into cholesterol-rich membrane rafts, with loss of LCMT1 producing soluble hyperphosphorylated Tau (PMID:21044074, PMID:23943618), while AB56αC heterotrimers dephosphorylate the androgen receptor and its coactivator MED1 to evict the complex from chromatin (PMID:37644036). The opposing actions of LCMT1 and the demethylase PME-1 establish a methylation equilibrium that governs mitotic spindle size and checkpoint fidelity and modulates neuronal sensitivity to amyloid-β (PMID:25839665, PMID:32341098). In vivo, LCMT1-mediated PP2A methylation controls insulin signaling, hepatic glycogen and lipid metabolism through autophagy, and glucose homeostasis (PMID:23840384, PMID:36963730, PMID:37579989). LCMT1 abundance is itself regulated post-translationally by HIF-1α-driven autophagic-lysosomal degradation and by S6K1/β-TRCP-mediated proteasomal degradation, the latter coupling LCMT1 loss to anti-androgen resistance (PMID:37644036, PMID:36555780).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2010 High

    Established that LCMT1 acts upstream of a defined PP2A holoenzyme to drive a cellular morphogenetic output, rather than being a generic housekeeping methyltransferase.

    Evidence LCMT1 overexpression/knockdown, methylation-incompetent PP2A mutant, Bα knockdown, and SAH/PME-1 perturbation in N2a neuroblastoma with neurite morphometry

    PMID:21044074

    Open questions at the time
    • Did not resolve which downstream cytoskeletal substrates the Bα holoenzyme acts on
    • Limited to a single neuroblastoma cell context
  2. 2011 High

    Resolved the structural basis for how LCMT1 recognizes PP2A and why methylation is coupled to phosphatase activation, explaining efficient conversion of active PP2A into substrate-specific holoenzymes.

    Evidence X-ray crystallography of LCMT1 alone and in complex with PP2A, in vitro methylation assays, and a dominant-negative cell-cycle mutant

    PMID:21292165

    Open questions at the time
    • Did not define how methylation selects among different B-subunit families
    • Cell-cycle role inferred from a dominant-negative without substrate-level detail
  3. 2012 Medium

    Placed LCMT1 within a signaling cascade by showing GSK-3β represses its activity to shift PP2A toward the demethylated state.

    Evidence GSK-3β overexpression/inhibition with PPMT1 (LCMT1) knockdown and dmL309-PP2Ac immunoblotting

    PMID:22732552

    Open questions at the time
    • No direct biochemical reconstitution of GSK-3β acting on LCMT1
    • Mechanism of inhibition (direct phosphorylation vs indirect) not established
  4. 2013 High

    Demonstrated that LCMT1-dependent methylation determines PP2A subcellular targeting, linking methylation to membrane raft localization and Tau dephosphorylation.

    Evidence Membrane microdomain fractionation, catalytically inactive LCMT1, siRNA, and one-carbon metabolism perturbation in N2a cells

    PMID:23943618

    Open questions at the time
    • The molecular determinant coupling methylation to raft partitioning is unresolved
    • Restricted to one cell line
  5. 2013 High

    Confirmed in vivo that LCMT1 is the sole PP2A methyltransferase in mammalian tissue and connected its activity to systemic insulin signaling.

    Evidence Hypomorphic Lcmt1 gene-trap mice with activity assays, PP2A methylation quantification, and insulin/glucose homeostasis tests

    PMID:23840384

    Open questions at the time
    • Tissue and substrate mediating the insulin-resistance phenotype not pinpointed
    • Hypomorphic, not null, model
  6. 2015 Medium

    Showed the LCMT1-PME-1 methylation equilibrium quantitatively tunes mitotic spindle size and checkpoint integrity.

    Evidence Reciprocal LCMT1/PME-1 gain- and loss-of-function with spindle measurements, SAC markers, and viability assays

    PMID:25839665

    Open questions at the time
    • No in vitro reconstitution of the spindle-size mechanism
    • Single lab; downstream PP2A holoenzyme on the spindle not identified
  7. 2016 High

    Broadened LCMT1's enzymatic scope to PP4 and PP6 and showed methylation selectively governs which regulatory-subunit complexes assemble.

    Evidence Methylation-specific antibodies, blue native PAGE of holoenzymes, LCMT1 knockout MEFs, and HDAC3 phospho-readout

    PMID:27507813

    Open questions at the time
    • Why PP4R1-PP4 is most methylation-sensitive is not mechanistically explained
    • Full substrate repertoire of PP4/PP6 methylation unmapped
  8. 2020 Medium

    Established that the LCMT1-PME-1 methylation balance sets neuronal vulnerability to amyloid-β, linking the axis to Alzheimer-relevant pathophysiology.

    Evidence Heterozygous LCMT1 gene-trap and PME-1 KO mice with cognitive behavior, LTP electrophysiology, and acute Aβ oligomer application

    PMID:32341098

    Open questions at the time
    • Did not identify the PP2A substrate responsible for Aβ sensitivity
    • Correlative genetic dosage rather than direct mechanism
  9. 2022 Medium

    Identified HIF-1α-driven autophagic-lysosomal degradation as a hypoxia-responsive route controlling LCMT1 protein levels and downstream Tau phosphorylation.

    Evidence HIF-1α overexpression/silencing in neurons and rats, LCMT1 promoter luciferase reporter, autophagy-lysosomal inhibitors, and PP2A activity/Tau readouts

    PMID:36555780

    Open questions at the time
    • Relative contribution of transcriptional vs degradative regulation not quantified
    • Autophagy receptor mediating LCMT1 turnover unknown
  10. 2023 High

    Defined a methylation-dependent AB56αC holoenzyme that dephosphorylates AR/MED1 and an S6K1/β-TRCP degradation pathway whose disruption confers anti-androgen resistance, establishing LCMT1 as a tractable target in prostate cancer.

    Evidence LCMT1 silencing, Co-IP of PP2A heterotrimers, AR/MED1 dephosphorylation and ChIP assays, S6K1/β-TRCP degradation dissection, SMAP stabilization, and in vivo tumor models

    PMID:37644036

    Open questions at the time
    • Whether SMAP-mediated LCMT1 stabilization is durable in vivo not fully resolved
    • Generality across other AR-dependent contexts untested
  11. 2023 Medium

    Demonstrated tissue-specific roles for hepatic LCMT1 in negatively regulating glycogen metabolism and in supporting autophagy to limit lipid accumulation.

    Evidence Liver-specific LCMT1 knockout mice with glycogen, GCK/glycogen-gene expression, glucose/insulin tolerance, autophagy flux, lipid staining, and MIHA/hepatocyte models

    PMID:36963730 PMID:37579989

    Open questions at the time
    • The specific PP2A holoenzyme and substrate controlling glycogen/autophagy outputs not identified
    • Reconciliation with whole-body insulin-resistance phenotype not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How methylation status is decoded to select among distinct B-subunit families to produce tissue- and substrate-specific PP2A/PP4/PP6 outputs remains unresolved.
  • No structural model of methyl-PP2A bound to competing B subunits
  • Substrate-level mediators of metabolic, mitotic, and neuronal phenotypes largely uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1430728 Metabolism 2 R-HSA-1640170 Cell Cycle 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-74160 Gene expression (Transcription) 1 R-HSA-9612973 Autophagy 1
Partners
B56ΑGSK-3ΒHIF-1ΑPME-1PP4R1PPP2CAS6K1Β-TRCP

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 Crystal structures of human LCMT-1 alone and in complex with PP2A (stabilized by a cofactor mimic) revealed that the LCMT-1 active-site pocket directly recognizes the carboxyl terminus of PP2A, and that the PP2A active site makes extensive contacts to LCMT-1. Activation of the PP2A active site was shown to stimulate methylation, suggesting a mechanism for efficient conversion of activated PP2A into substrate-specific holoenzymes. A dominant-negative LCMT-1 mutant attenuated the cell cycle without causing cell death. X-ray crystallography of LCMT-1 alone and in complex with PP2A; in vitro methylation assays; dominant-negative mutant cell cycle assays Molecular cell High 21292165
2016 LCMT-1 is the major carboxyl methyltransferase not only for PP2A but also for PP4 and PP6 catalytic subunits in mouse embryonic fibroblasts (MEFs). LCMT-1 loss differentially disrupts PP4 holoenzyme complexes (PP4R1-containing complex most dramatically affected), reduces steady-state levels of PP2A B and PP4R1 regulatory subunits, and causes hyperphosphorylation of HDAC3, a target of the methylation-dependent PP4R1-PP4 complex. Antibodies specific for unmethylated phosphatases; blue native PAGE analysis of holoenzyme complexes; LCMT-1 knockout MEFs; immunoblotting for HDAC3 phosphorylation The Journal of biological chemistry High 27507813
2010 Enhanced LCMT1 expression in N2a neuroblastoma cells increases methylated PP2A C subunit and PP2A/Bα levels, induces F-actin reorganization, and promotes serum-independent neuritogenesis and tau-positive process formation. These effects are blocked by LCMT1 knockdown, the methylation inhibitor SAH, expression of PME-1, or a methylation-incompetent PP2A mutant (L309Δ), and by Bα knockdown, establishing a LCMT1→PP2A methylation→Bα holoenzyme→neurite outgrowth pathway. LCMT1 overexpression and siRNA knockdown; inducible Bα knockdown; methylation-incompetent PP2A mutant; pharmacological inhibition with SAH; F-actin staining; neurite morphometry Journal of neurochemistry High 21044074
2013 LCMT1-dependent methylation of PP2A controls the association of methylated PP2A and Bα holoenzymes with cholesterol-rich plasma membrane rafts in N2a cells. A methylation-incompetent PP2A mutant is excluded from rafts. Knockdown or catalytic inactivation of LCMT1, or perturbation of one-carbon metabolism, causes loss of membrane-associated PP2A and Tau and accumulation of soluble phosphorylated Tau. Subcellular fractionation of membrane microdomains/rafts; catalytically inactive LCMT1 mutant; LCMT1 siRNA knockdown; one-carbon metabolism perturbation; immunoblotting for methylated/phosphorylated PP2A and Tau The Journal of biological chemistry High 23943618
2013 Hypomorphic Lcmt1 gene-trap mice with reduced LCMT1 protein and activity showed proportionally reduced PP2A carboxyl methylation, indicating LCMT1 is the sole PP2A methyltransferase in mammalian tissues. These mice exhibit an insulin-resistance phenotype, linking LCMT1-dependent PP2A methylation to insulin signaling in vivo. Gene-trap mouse model; LCMT1 activity assays; PP2A methylation quantification; insulin tolerance and glucose homeostasis assays in vivo PloS one High 23840384
2015 The LCMT1–PME-1 methylation equilibrium controls mitotic spindle size. Depletion of LCMT1 produced long spindles; overexpression of LCMT1 produced short spindles. Disruption of this equilibrium caused mitotic arrest, spindle assembly checkpoint activation, defective cell divisions, and apoptosis. siRNA depletion of LCMT1; LCMT1 overexpression; PME-1 depletion and overexpression; spindle size measurements; spindle assembly checkpoint markers; cell viability assays Cell cycle (Georgetown, Tex.) Medium 25839665
2012 GSK-3β inhibits LCMT1 (PPMT1) activity, resulting in increased demethylation of PP2A at Leu-309. Knockdown of PPMT1 eliminated the effects of GSK-3β on PP2A demethylation, placing LCMT1 downstream of GSK-3β in a pathway that controls PP2A methylation status and PP2A regulatory subunit levels. GSK-3β overexpression/inhibition; PPMT1 siRNA knockdown; immunoblotting for dmL309-PP2Ac; PP2A regulatory subunit quantification FEBS letters Medium 22732552
2023 LCMT1 methylates the L309 residue of the PP2A C subunit, and this methylation enables formation of AB56αC heterotrimers that dephosphorylate the androgen receptor (AR) and its coactivator MED1, causing eviction of the AR-MED1 complex from chromatin. LCMT1 is degraded via S6K1-mediated phosphorylation-induced proteasomal degradation requiring β-TRCP, and this degradation drives resistance to anti-androgens. Small-molecule SMAP stabilizes LCMT1 and attenuates AR signaling. LCMT1 silencing; Co-IP/interaction assays for PP2A heterotrimers; dephosphorylation assays for AR and MED1; chromatin immunoprecipitation; S6K1 overexpression/inhibition; β-TRCP interaction; SMAP treatment; in vivo tumor models Nature communications High 37644036
2022 HIF-1α, induced by chronic hypoxia, decreases LCMT1 protein levels by promoting LCMT1 degradation via the autophagy–lysosomal pathway, thereby reducing PP2A methylation and activity and leading to tau hyperphosphorylation. Dual luciferase assay showed HIF-1α also acts as a transcription factor at the LCMT1 promoter, but the net effect of HIF-1α is LCMT1 protein reduction. HIF-1α overexpression and siRNA silencing in neurons and rats; dual luciferase reporter assay for LCMT1 promoter; autophagy–lysosomal inhibitor experiments; LCMT1 and PP2A activity measurements; tau phosphorylation immunoblotting International journal of molecular sciences Medium 36555780
2023 Liver-specific LCMT1 knockout increases hepatic glycogen synthesis and accumulation, reverses high-fat diet-induced downregulation of glucokinase (GCK) and glycogen synthesis genes, and improves glucose intolerance and insulin resistance, establishing that hepatic LCMT1-mediated PP2A methylation negatively regulates glycogen metabolism and glucose homeostasis. Liver-specific LCMT1 knockout mouse model; glycogen content assays; GCK and glycogen synthesis gene expression; glucose and insulin tolerance tests; siRNA in MIHA cells The Journal of nutritional biochemistry Medium 36963730
2023 LCMT1-mediated PP2Ac methylation regulates autophagy; liver-specific LCMT1 knockout in mice and BaP-treated primary hepatocytes showed that loss of LCMT1 activity reduces PP2Ac methylation and inhibits autophagy, leading to hepatic lipid accumulation. Liver-specific LCMT1 KO mouse model; primary hepatocyte treatment with BaP; autophagy flux assays; PP2Ac methylation immunoblotting; lipid staining Food and chemical toxicology Medium 37579989
2020 Reducing endogenous LCMT-1 expression (heterozygous gene-trap mice) increased sensitivity to Aβ-induced cognitive and synaptic plasticity impairments, while reducing PME-1 expression was protective, establishing that the LCMT1–PME-1 balance in PP2A methylation modulates neuronal sensitivity to Aβ. Heterozygous LCMT-1 gene-trap mice; heterozygous PME-1 KO mice; behavioral cognition assays; electrophysiological LTP recordings; acute Aβ oligomer application The Journal of neuroscience Medium 32341098

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 The structural basis for tight control of PP2A methylation and function by LCMT-1. Molecular cell 123 21292165
2010 Regulation of protein phosphatase 2A methylation by LCMT1 and PME-1 plays a critical role in differentiation of neuroblastoma cells. Journal of neurochemistry 45 21044074
2016 Leucine Carboxyl Methyltransferase 1 (LCMT-1) Methylates Protein Phosphatase 4 (PP4) and Protein Phosphatase 6 (PP6) and Differentially Regulates the Stable Formation of Different PP4 Holoenzymes. The Journal of biological chemistry 43 27507813
2013 Leucine carboxyl methyltransferase 1 (LCMT1)-dependent methylation regulates the association of protein phosphatase 2A and Tau protein with plasma membrane microdomains in neuroblastoma cells. The Journal of biological chemistry 42 23943618
2018 Protein Phosphatase 2A and Its Methylation Modulating Enzymes LCMT-1 and PME-1 Are Dysregulated in Tauopathies of Progressive Supranuclear Palsy and Alzheimer Disease. Journal of neuropathology and experimental neurology 40 29281045
2012 Glycogen synthase kinase-3β regulates leucine-309 demethylation of protein phosphatase-2A via PPMT1 and PME-1. FEBS letters 34 22732552
2022 HIF-1α Causes LCMT1/PP2A Deficiency and Mediates Tau Hyperphosphorylation and Cognitive Dysfunction during Chronic Hypoxia. International journal of molecular sciences 30 36555780
2023 Loss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance. Nature communications 18 37644036
2023 Low-dose benzo[a]pyrene exposure induces hepatic lipid deposition through LCMT1/PP2Ac-mediated autophagy inhibition. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 14 37579989
2019 Functional characterization of metallothionein-like genes from Physcomitrella patens: expression profiling, yeast heterologous expression, and disruption of PpMT1.2a gene. Planta 12 31037485
2015 A LCMT1-PME-1 methylation equilibrium controls mitotic spindle size. Cell cycle (Georgetown, Tex.) 12 25839665
2013 Circumventing embryonic lethality with Lcmt1 deficiency: generation of hypomorphic Lcmt1 mice with reduced protein phosphatase 2A methyltransferase expression and defects in insulin signaling. PloS one 12 23840384
2019 Proteomics and phosphoproteomics study of LCMT1 overexpression and oxidative stress: overexpression of LCMT1 arrests H2O2-induced lose of cells viability. Redox report : communications in free radical research 6 30898057
2020 Reduced Expression of the PP2A Methylesterase, PME-1, or the PP2A Methyltransferase, LCMT-1, Alters Sensitivity to Beta-Amyloid-Induced Cognitive and Electrophysiological Impairments in Mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 5 32341098
2023 Hepatic leucine carboxyl methyltransferase 1 (LCMT1) contributes to high fat diet-induced glucose intolerance through regulation of glycogen metabolism. The Journal of nutritional biochemistry 3 36963730
2025 PP2A methylesterase, PME-1, and PP2A methyltransferase, LCMT-1, control sensitivity to impairments caused by injury-related oligomeric tau. Alzheimer's & dementia : the journal of the Alzheimer's Association 2 41388803

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