Affinage

TLL1

Tolloid-like protein 1 · UniProt O43897

Length
1013 aa
Mass
114.7 kDa
Annotated
2026-06-10
20 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TLL1 is a secreted astacin-like metalloprotease that acts extracellularly to process precursor and latent substrates governing matrix assembly, morphogenetic signaling, and tissue homeostasis (PMID:10331975, PMID:12808086). It is essential for heart development: Tll1-null embryos die from cardiac failure with incomplete interventricular septum formation, a role distinct from BMP1, which is not co-expressed in this tissue (PMID:10331975). Together with BMP1 it provides in vivo procollagen C-proteinase activity and cleaves the BMP antagonist Chordin, linking it to BMP signaling (PMID:12808086), and combined Bmp1/Tll1 ablation impairs processing of procollagen and dentin matrix protein 1 (DMP1), producing osteogenesis imperfecta, defective osteocyte maturation, and periodontal and dentin defects (PMID:24419319, PMID:28068493, PMID:28000152). TLL1 also cleaves SLIT2 at a defined site to control sensory axon fasciculation, and this proteolysis requires prior furin/prohormone-convertase activation of TLL1 (PMID:41626796). Beyond matrix substrates, TLL1 activates TGF-β signaling by cleaving latent TGF-β1, promoting prostate cancer migration, metastasis, and PD-L1-mediated immune evasion, and contributing to bacterial adhesion in intestinal epithelium (PMID:36087399, PMID:40760092). Its activity is tuned by calcium-dependent dimerization through its non-catalytic domains, which restricts substrate access (PMID:20043912). A gain-of-function catalytic-domain mutation (p.T253A) that prolongs active-enzyme half-life causes autosomal dominant mitral valve prolapse (PMID:39880331).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1999 High

    Established TLL1 as a non-redundant developmental metalloprotease by showing it is required for cardiac interventricular septum formation in a tissue where BMP1 is absent, defining a unique in vivo role.

    Evidence Gene knockout in mice with in situ expression analysis and embryological phenotyping

    PMID:10331975

    Open questions at the time
    • Molecular substrate driving the cardiac phenotype not identified
    • Mechanistic link between protease activity and septum morphogenesis unresolved
  2. 2003 High

    Resolved the biochemical activity of TLL1 by demonstrating it functions in vivo as a procollagen C-proteinase and, with BMP1, cleaves the BMP antagonist Chordin, placing it in collagen maturation and BMP signaling.

    Evidence Bmp1/Tll1 double-null mouse embryos with biochemical pCP assays and proteomics substrate identification

    PMID:12808086

    Open questions at the time
    • Relative substrate preference of TLL1 vs BMP1 not quantified
    • Tissue contexts of Chordin cleavage not mapped
  3. 2009 Medium

    Explained how TLL1 activity is regulated by showing calcium-dependent side-by-side dimerization through non-catalytic domains imposes a substrate-exclusion mechanism that lowers activity toward Chordin.

    Evidence Structural/biochemical analysis with truncation mutants and chordin activity assays

    PMID:20043912

    Open questions at the time
    • No crystal or cryo-EM structure reported
    • Physiological trigger for dimer-monomer transition unknown
    • Single-lab in vitro data
  4. 2016 Medium

    Extended TLL1 substrate processing to tooth and supporting tissues, showing it is required for dentin and periodontal ligament development via procollagen and DSPP processing.

    Evidence Col1a1-Cre conditional Bmp1/Tll1 double knockout with radiography, histology, immunohistochemistry

    PMID:28000152

    Open questions at the time
    • TLL1-specific contribution separate from BMP1 not dissected
    • Direct DSPP cleavage by TLL1 not shown biochemically
  5. 2014 High

    Demonstrated a postnatal homeostatic role by showing combined loss causes osteogenesis imperfecta with impaired procollagen and DMP1 processing, defective osteocyte maturation, and altered sclerostin/Wnt signaling.

    Evidence Inducible conditional double knockout with bone histology, biochemical processing assays, and Wnt reporters

    PMID:24419319

    Open questions at the time
    • Whether DMP1 is a direct TLL1 substrate not biochemically isolated
    • TLL1 versus BMP1 individual contributions not separated
  6. 2017 High

    Confirmed TLL1's role in periodontal homeostasis through procollagen I and DMP1 processing, with progressive ligament and alveolar bone defects.

    Evidence Conditional double knockout mice with histology, immunohistochemistry, and antibiotic rescue

    PMID:28068493

    Open questions at the time
    • TLL1-specific function not isolated from BMP1
    • Mechanism connecting substrate processing to bone loss incomplete
  7. 2022 Medium

    Placed TLL1 upstream of TGF-β signaling in epithelial cells, linking it to bacterial adhesion and invasion.

    Evidence shRNA knockdown in Caco-2 cells with invasion assays, TGF-β inhibitor, and transcriptome sequencing

    PMID:36087399

    Open questions at the time
    • Direct substrate connecting TLL1 to TGF-β activation not identified here
    • Single cell line and single lab
  8. 2025 Medium

    Defined a TGF-β-activating mechanism by showing TLL1 cleaves latent TGF-β1 to drive prostate cancer metastasis and PD-L1-mediated immune evasion.

    Evidence TLL1 knockdown/overexpression in prostate cancer cells and mouse models with TGF-β assays, immune infiltration analysis, and anti-PD-1 treatment

    PMID:40760092

    Open questions at the time
    • Direct biochemical cleavage of latent TGF-β1 by purified TLL1 not shown
    • Generality across cancers untested
    • Single lab
  9. 2025 Medium

    Established a disease mechanism for mitral valve prolapse via a gain-of-function catalytic mutation that prolongs active-enzyme half-life.

    Evidence Whole exome/genome sequencing with segregation and in vitro enzymatic activity comparison of WT vs p.T253A in HEK293 cells

    PMID:39880331

    Open questions at the time
    • Tissue substrate driving MVP not identified
    • In vivo validation of the gain-of-function allele lacking
    • Single lab
  10. 2026 High

    Identified SLIT2 as a direct TLL1 substrate and established furin-dependent activation, linking TLL1 cleavage to sensory axon fasciculation.

    Evidence Cell-based cleavage assay, CRISPR Slit2ΔTLS knock-in mice, in vivo DRG axon guidance, and in vitro fasciculation assays

    PMID:41626796

    Open questions at the time
    • Structural basis of SLIT2 recognition not resolved
    • Other neural contexts of TLL1-SLIT2 cleavage unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved which direct substrate(s) of TLL1 drive each tissue-specific phenotype and how dimerization, furin activation, and calcium regulation are coordinated in vivo to select among collagen, Chordin, SLIT2, and latent TGF-β1 substrates.
  • No integrated structural model of substrate selection
  • Direct biochemical demonstration lacking for DMP1, DSPP, and latent TGF-β1
  • TLL1-specific versus BMP1-redundant contributions not systematically separated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016787 hydrolase activity 3 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005576 extracellular region 2 GO:0031012 extracellular matrix 2
Pathway
R-HSA-1474244 Extracellular matrix organization 4 R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2
Partners
BMP1CHRDDMP1FURINSLIT2TGFB1

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 TLL1 (mTLL-1) is an astacin-like metalloprotease expressed specifically in precardiac tissue and endocardium; genetic knockout (Tll1-/-) causes embryonic lethality from cardiac failure with incomplete muscular interventricular septum formation and abnormal heart/aorta positioning, establishing TLL1 as essential for interventricular septum formation in a tissue where Bmp1 is not expressed. Gene targeting/knockout in ES cells, in situ expression analysis, embryological phenotyping Development (Cambridge, England) High 10331975
2003 Using Bmp1/Tll1 doubly homozygous null mice, mTLL-1 was demonstrated to be an in vivo procollagen C-proteinase (pCP) providing residual pCP activity observed in Bmp1-/- embryos, and together with BMP-1, is responsible for in vivo cleavage of Chordin (an extracellular BMP-signaling antagonist) in mammals. Bmp1/Tll1 double knockout mouse embryos, biochemical analysis of pCP activity, proteomics-based substrate identification Molecular and cellular biology High 12808086
2009 TLL-1 forms a calcium-ion dependent dimer with monomers stacked side-by-side; truncated TLL-1 molecules with the same shorter structure as BMP-1 are monomers and show improved (higher) activity toward chordin substrate, exceeding both full-length TLL-1 and BMP-1, demonstrating a substrate exclusion mechanism dependent on the non-catalytic domains and dimerization. Structural and biochemical analysis, truncation mutants, activity assay toward chordin substrate FEBS letters Medium 20043912
2014 Induced postnatal simultaneous ablation of Bmp1 and Tll1 in mice causes osteogenesis imperfecta with spontaneous fractures, osteomalacia, reduced processing of procollagen and dentin matrix protein 1 (DMP1), high bone turnover, and defective osteocyte maturation with decreased sclerostin expression and induced canonical Wnt signaling, demonstrating that TLL1 (together with BMP1) processes procollagen and DMP1 in bone. Conditional double knockout mouse model (floxed alleles), bone histology, biochemical assays for procollagen processing, immunohistochemistry for DMP1 and sclerostin, Wnt signaling reporters Human molecular genetics High 24419319
2017 Conditional double ablation of Bmp1 and Tll1 causes progressive periodontal defects including malformed periodontal ligament, alveolar bone loss, and reduced cellular cementum, accompanied by increased uncleaved procollagen I precursor and reduced DMP1, demonstrating TLL1 and BMP1 are required for procollagen I and DMP1 processing in periodontal homeostasis. Conditional double knockout mice, histology, immunohistochemistry, molecular analysis of procollagen processing and DMP1 levels, antibiotic rescue experiment Journal of dental research High 28068493
2016 Inactivation of both Bmp1 and Tll1 in type I collagen-expressing cells causes wider predentin, thinner dentin, disorganized dentinal tubules, reduced dentin sialophosphoprotein (DSPP), and disorganized periodontal ligament with less fibrillin-1, establishing roles for TLL1 in dentin and periodontal ligament development. Col1a1-Cre driven conditional double knockout, X-ray radiography, histology, immunohistochemistry Journal of molecular histology Medium 28000152
2022 TLL1 knockdown (shRNA) in intestinal epithelial Caco-2 cells significantly reduced K. pneumoniae adhesion and invasion; TLL1 was found to participate in activation of the TGF-β signaling pathway, and inhibition of this pathway reduced bacterial adhesion/invasion, placing TLL1 upstream of TGF-β signaling in this context. shRNA knockdown, bacterial invasion/adhesion assays, TGF-β pathway inhibitor (SB431542), transcriptome sequencing International journal of medical microbiology : IJMM Medium 36087399
2025 TLL1 promotes prostate cancer cell migration and metastasis by cleaving latent TGF-β1 to activate TGF-β signaling; TLL1 also increases PD-L1 expression via TGF-β signaling activation, and TLL1 depletion enhances anti-PD-1 antibody antitumor efficacy by augmenting CD8+ T cell infiltration. T cell-specific TLL1 overexpression disrupts thymic T cell development and accelerates tumor growth in mice. TLL1 knockdown/overexpression in prostate cancer cells and mouse models, TGF-β signaling assays, immune cell infiltration analysis, anti-PD-1 treatment experiments Oncogene Medium 40760092
2025 A missense mutation p.T253A in the catalytic domain of TLL1 causes autosomal dominant mitral valve prolapse (MVP); the mutant TLL1 protein has 3.4-fold higher enzymatic activity over 12 hours compared to wild-type in HEK293 cell media, indicating a gain-of-function with prolonged half-life of active extracellular TLL1 causing MVP. Whole exome/genome sequencing with Sanger segregation analysis, in vitro enzymatic activity assay in HEK293-transfected cells comparing wild-type vs mutant TLL1 The Canadian journal of cardiology Medium 39880331
2026 TLL1 protease cleaves SLIT2 (a secreted axon repellent) in cultured cells at a defined TLL1 cleavage site (TLS); TLL1 requires activation by furin/prohormone convertases. CRISPR-edited Slit2ΔTLS mice lacking the TLL1 cleavage site showed reduced fasciculation of DRG axon rootlets and longitudinal projections (without losing dorsal repulsion), and SLIT2-N fragment promoted in vitro DRG axon fasciculation, identifying SLIT2 as a TLL1 substrate and establishing a functional consequence of this cleavage. Cell-based cleavage assay, CRISPR knock-in mouse model (Slit2ΔTLS), in vivo DRG axon guidance analysis, in vitro axon fasciculation assay Development (Cambridge, England) High 41626796

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 The mammalian Tolloid-like 1 gene, Tll1, is necessary for normal septation and positioning of the heart. Development (Cambridge, England) 110 10331975
2017 Genome-Wide Association Study Identifies TLL1 Variant Associated With Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection. Gastroenterology 108 28163062
2003 Use of Bmp1/Tll1 doubly homozygous null mice and proteomics to identify and validate in vivo substrates of bone morphogenetic protein 1/tolloid-like metalloproteinases. Molecular and cellular biology 97 12808086
2014 Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice. Human molecular genetics 58 24419319
2021 PNPLA3 and TLL-1 Polymorphisms as Potential Predictors of Disease Severity in Patients With COVID-19. Frontiers in cell and developmental biology 24 34249902
2017 BMP1 and TLL1 Are Required for Maintaining Periodontal Homeostasis. Journal of dental research 23 28068493
2021 Association between Interferon-Lambda-3 rs12979860, TLL1 rs17047200 and DDR1 rs4618569 Variant Polymorphisms with the Course and Outcome of SARS-CoV-2 Patients. Genes 22 34071309
2009 Structural and functional evidence for a substrate exclusion mechanism in mammalian tolloid like-1 (TLL-1) proteinase. FEBS letters 18 20043912
2016 Inactivation of bone morphogenetic protein 1 (Bmp1) and tolloid-like 1 (Tll1) in cells expressing type I collagen leads to dental and periodontal defects in mice. Journal of molecular histology 14 28000152
2020 Possible Relevance of PNPLA3 and TLL1 Gene Polymorphisms to the Efficacy of PEG-IFN Therapy for HBV-Infected Patients. International journal of molecular sciences 11 32349377
2019 TLL1 variants do not predict hepatocellular carcinoma development in HCV cirrhotic patients treated with direct-acting antivirals. Journal of viral hepatitis 11 31177595
2022 Klebsiella pneumoniae activates the TGF-β signaling pathway to adhere to and invade intestinal epithelial cells via enhancing TLL1 expression. International journal of medical microbiology : IJMM 10 36087399
2020 Genetic variation in the TLL1 gene is not associated with fibrosis in patients with metabolic associated fatty liver disease. PloS one 7 33306709
2023 Assessment of TLL1 variant and risk of hepatocellular carcinoma in Latin Americans and Europeans. Annals of hepatology 5 37981236
2025 Mitral Valve Prolapse Caused by TLL1 Gain-of-Function Mutation. The Canadian journal of cardiology 4 39880331
2022 Deciphering complex rearrangements at the breakpoint of an apparently balanced reciprocal translocation t(4:18)(q31;q11.2)dn and at a cryptic deletion: Further evidence of TLL1 as a causative gene for atrial septal defect. American journal of medical genetics. Part A 4 35567499
2014 Association of TLL1 gene polymorphism (rs1503298, T > C) with coronary heart disease in PREDICT, UDACS and ED cohorts. Journal of the College of Physicians and Surgeons--Pakistan : JCPSP 4 25233961
2005 ASD--lessons on genetic background from transgenic mice with inactive gene encoding metalloprotease, Tolloid-like 1 (TLL1). Medical science monitor : international medical journal of experimental and clinical research 4 16369476
2025 TLL1 knockdown attenuates prostate cancer progression by enhancing antitumor immunity. Oncogene 1 40760092
2026 SLIT2 repellent is cleaved by TLL1 protease and promotes sensory axon fasciculation. Development (Cambridge, England) 0 41626796

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