Affinage

BMP1

Bone morphogenetic protein 1 · UniProt P13497

Length
986 aa
Mass
111.2 kDa
Annotated
2026-06-09
100 papers in source corpus 34 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BMP1 is a secreted astacin-family zinc metalloproteinase that serves as the principal procollagen C-proteinase, cleaving the C-propeptides of fibrillar procollagens I–III to drive collagen fibril assembly in the extracellular matrix; loss of its catalytic activity in mice produces aberrant collagen fibril morphology and failure of ventral body wall closure (PMID:8951074), and in humans biallelic BMP1 mutations cause autosomal recessive osteogenesis imperfecta with defective C-propeptide processing and impaired heterotypic type I/V collagen fibril assembly (PMID:22052668, PMID:22482805, PMID:25656619). It is synthesized as an inactive zymogen whose prodomain is removed by furin-like proprotein convertases in the trans-Golgi network to generate the mature enzyme (PMID:12637537, PMID:12637569). Beyond procollagens, BMP1 is a broad-specificity ECM-remodeling protease: it cleaves Chordin to release BMP2/4 and antagonize dorsalizing signals (PMID:10479448), activates latent myostatin by cleaving its propeptide (PMID:14671324), processes LTBP1 to liberate latent TGF-β in a TGF-β-inducible feed-forward loop (PMID:17015622), activates lysyl oxidases LOX and LOXL1 by propeptide removal (PMID:31152061, PMID:35328709), matures decorin/biglycan and the dentin proteins DSPP/DMP1 (PMID:20026052, PMID:20079836), releases the angiostatic LG3 fragment from endorepellin/perlecan (PMID:15591058) and endotrophin from collagen VI α3 (PMID:31346034), and cleaves thrombospondin-1 and the TGF-β co-receptors betaglycan and CD109 to potentiate SMAD2 signaling (PMID:25260970, PMID:32636307). It also acts in lipid metabolism, maturing pro-apoA1 for functional HDL formation and cleaving LDLR to reduce LDL uptake in hepatocytes (PMID:17580958, PMID:37235726). Substrate selectivity and catalytic efficiency are governed by the non-catalytic CUB1 and CUB2 domains—the isolated protease domain loses specificity and over-digests substrates, while CUB1 is additionally required for secretion and CUB2 (residue Glu-483) for procollagen cleavage (PMID:12637537, PMID:15817489, PMID:17516847). Activity is positively modulated by PCPE-1 (specific to fibrillar procollagens), periostin, and WFIKKN1, and negatively regulated by PCPE-2, sizzled, and α2-macroglobulin (PMID:15834133, PMID:20181949, PMID:27782377, PMID:38049428, PMID:22825851). BMP1 functions redundantly with the related protease mTLL-1/TLL1, and combined ablation is required to fully remove procollagen and Chordin processing in vivo (PMID:12808086, PMID:24419319).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1996 High

    Established that BMP1 is the in vivo procollagen C-proteinase whose activity is required for normal collagen fibril formation, defining its core ECM function.

    Evidence Bmp1 active-site null mice with metabolic labeling, immunofluorescence, and electron microscopy of ECM

    PMID:8951074

    Open questions at the time
    • Residual procollagen processing in nulls implied additional redundant proteases
    • Did not define which non-collagen substrates contribute to the body-wall phenotype
  2. 1999 High

    Extended BMP1 substrate repertoire beyond collagen to Chordin, linking the protease to BMP2/4 signaling and dorsoventral patterning while distinguishing it from related family members.

    Evidence In vitro cleavage assays and Xenopus dorsalization/rescue assays across four BMP1/TLD proteases

    PMID:10479448

    Open questions at the time
    • In vivo mammalian contribution of each family member to Chordin cleavage not yet resolved
  3. 2003 High

    Resolved the redundancy between BMP1 and mTLL-1, showing both are jointly responsible for Chordin and residual procollagen processing in mammals.

    Evidence Bmp1/Tll1 double-knockout mouse embryos with biochemical and proteomic analysis

    PMID:12808086

    Open questions at the time
    • Relative contribution of each protease in specific tissues not quantified
  4. 2003 High

    Defined how BMP1 itself is activated—prodomain removal by furin-like convertases in the TGN—and the minimal/essential domain architecture for procollagen cleavage and secretion.

    Evidence Furin inhibition, recombinant furin cleavage, RSRR-site mutagenesis, domain deletion/swap, secretion and cleavage assays, immunofluorescence

    PMID:12637537 PMID:12637569

    Open questions at the time
    • No high-resolution structure of the proenzyme or CUB-substrate interface
    • Functional role of individual PTMs untested
  5. 2003 High

    Identified latent myostatin as a BMP1 substrate, establishing a role in regulating muscle mass.

    Evidence In vitro cleavage of myostatin propeptide, cleavage-resistant mutant, in vivo injection into adult mice

    PMID:14671324

    Open questions at the time
    • Physiological setting and tissue context of endogenous myostatin activation by BMP1 not defined
  6. 2004 High

    Showed BMP1 releases the angiostatic LG3 fragment from perlecan/endorepellin, connecting the protease to angiogenesis control.

    Evidence In vitro and cell-based endorepellin cleavage, mutagenesis, angiogenic assays, modeling

    PMID:15591058

    Open questions at the time
    • In vivo requirement for BMP1 in LG3 generation and angiogenesis not established
  7. 2005 High

    Mapped the determinants of BMP1 substrate selectivity—CUB domains and PCPE-1 specificity—distinguishing fibrillar procollagen processing from Chordin cleavage.

    Evidence Domain swaps between BMP1 and mTLL-2, PCPE-1 enhancement across multiple substrates, procollagen conformational variants

    PMID:15817489 PMID:15834133

    Open questions at the time
    • Structural basis of CUB1-conferred Chordin specificity not solved
  8. 2006 High

    Connected BMP1 to TGF-β mobilization via LTBP1 cleavage and revealed a TGF-β-inducible feed-forward loop in tissue remodeling.

    Evidence In vitro LTBP1 cleavage, MEF cultures, MMP2 inhibitor/genetic experiments, in vivo evidence

    PMID:17015622

    Open questions at the time
    • BMP1 liberates the latent complex but does not directly activate TGF-β; downstream activation depends on other proteases
  9. 2007 Medium

    Demonstrated that non-catalytic domains, not the protease domain alone, enforce physiological substrate specificity, and broadened substrates into lipoprotein metabolism via pro-apoA1.

    Evidence Full-length vs. isolated protease domain on multiple substrates; recombinant/antibody/siRNA assays for pro-apoA1 in HepG2 and CHO cells

    PMID:17516847 PMID:17580958

    Open questions at the time
    • pro-apoA1 work from single lab, in vivo HDL relevance untested
    • No residue-level mapping of CUB selectivity contacts
  10. 2010 High

    Established positive cofactor and substrate links in collagen cross-linking: periostin enhances BMP1-mediated LOX activation, and BMP1 processes DSPP.

    Evidence Co-IP and solid-phase binding, periostin-null osteoblasts; in vitro DSPP cleavage with motif mutagenesis across three isoforms

    PMID:20079836 PMID:20181949

    Open questions at the time
    • Mechanism of periostin-mediated ECM deposition of BMP1 only partially defined
  11. 2011 High

    Established BMP1 mutation as a cause of human autosomal recessive osteogenesis imperfecta through loss of procollagen C-propeptide processing.

    Evidence Patient fibroblast processing assays, WT vs. mutant mTLD overexpression, homozygosity mapping

    PMID:22052668

    Open questions at the time
    • Genotype-phenotype range across BMP1 mutations not fully defined at this stage
  12. 2012 High

    Linked BMP1 to bone matrix maturation and high-bone-mass OI phenotypes, with conserved osteogenic function in zebrafish.

    Evidence Whole-exome sequencing, secretion assays, zebrafish bmp1a mutants, bone histology/biochemistry

    PMID:22482805

    Open questions at the time
    • Mechanism linking impaired secretion to increased bone mineral density not fully resolved
  13. 2014 High

    Defined the in vivo skeletal consequences of combined BMP1/TLL1 loss and broadened TGF-β pathway regulation through betaglycan and CD109 cleavage.

    Evidence Conditional Bmp1/Tll1 double KO skeletal phenotyping; iTRAQ proteomics, in vitro cleavage with MS site mapping, SMAD2 assays in primary keratocytes

    PMID:24419319 PMID:25260970

    Open questions at the time
    • Mechanism linking BMP1 loss to canonical Wnt induction in bone not established
    • Net signaling outcome of co-receptor cleavage may be context-dependent
  14. 2015 High

    Confirmed in humans that BMP1 deficiency impairs both procollagen and prodecorin processing, disrupting heterotypic collagen fibril assembly.

    Evidence Patient fibroblast processing assays, immunofluorescence for collagens I/V, dermal TEM

    PMID:25656619

    Open questions at the time
    • Quantitative contribution of decorin defect vs. collagen defect to the phenotype unresolved
  15. 2016 High

    Defined tissue-level skin phenotypes of BMP1-like proteinase loss and enumerated cofactor PTMs and a positive enhancer (WFIKKN1) for myostatin processing.

    Evidence Conditional Bmp1/Tll1 KO skin with histology/EM/wound healing and multi-substrate processing; LC-MS/MS PTM mapping; in vitro WFIKKN1 enhancer assays

    PMID:26944735 PMID:27363389 PMID:27782377

    Open questions at the time
    • Functional role of identified PTMs untested by mutagenesis
    • Collagen VII processing attributed to non-BMP1 proteases
  16. 2019 High

    Refined lysyl oxidase activation and added collagen VI/endotrophin to the substrate set, showing coordinated processing with ADAMTS and furin proteases.

    Evidence Cellular models, immunoprecipitation, LOX activity and binding assays, isotopic MS site mapping, EM/immunofluorescence

    PMID:31152061 PMID:31346034

    Open questions at the time
    • Physiological balance between BMP1 and ADAMTS cleavage of LOX/LOXL1 in vivo unclear
  17. 2020 High

    Established BMP1 as the major nonredundant procollagen C-proteinase in lung fibroblasts and extended its TGF-β-modulating role via thrombospondin-1 cleavage.

    Evidence Bmp1 KO/siRNA/inhibitor in murine and human lung fibroblasts with CICP ELISA; TSP-1 cleavage with adhesion, SMAD reporter, and ECM fractionation assays

    PMID:32636307 PMID:33206546

    Open questions at the time
    • Tissue specificity of BMP1 nonredundancy vs. mTLL-1 not generalized beyond lung fibroblasts
  18. 2022 Medium

    Tested and refuted a requirement for BMP1 in bleomycin-induced lung fibrosis and resolved differential LOXL1 cleavage between BMP1 and ADAMTS14.

    Evidence Inducible Bmp1 cKO in bleomycin model with CICP measurement; cellular genetic models and proteomics for LOXL1

    PMID:35328709 PMID:35361882

    Open questions at the time
    • Negative fibrosis result from single lab/model; redundancy with mTLL-1 may mask requirement
    • Functional consequences of distinct LOXL1 cleavage products not defined
  19. 2023 High

    Extended BMP1 into lipid receptor metabolism via hepatic LDLR cleavage, and clarified the regulatory network with the inhibitor PCPE-2 and an O-fucosylation-dependent secretion/Chordin axis.

    Evidence Hepatocyte inhibition/knockdown of astacin proteases, LDLR site mutagenesis, LDL uptake assays; PCPE-2 binding and multi-substrate inhibition assays; poFUT1 manipulation with BMP1-CHRD binding and SMAD readouts in endometrial stromal cells

    PMID:37235726 PMID:37338142 PMID:38049428

    Open questions at the time
    • In vivo cholesterol/HDL phenotypes of BMP1-mediated LDLR cleavage untested
    • O-fucosylation findings from single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How BMP1's CUB domains and cofactors structurally select among its many substrates, and what determines tissue-specific nonredundancy versus mTLL-1, remain unresolved.
  • No structural model of CUB-substrate recognition
  • In vivo hierarchy of physiological substrates not ranked
  • Tissue determinants of BMP1 vs. mTLL-1 redundancy unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0016787 hydrolase activity 3 GO:0140097 catalytic activity, acting on DNA 1
Localization
GO:0005576 extracellular region 4 GO:0031012 extracellular matrix 4 GO:0005794 Golgi apparatus 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-1474244 Extracellular matrix organization 5 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-1266738 Developmental Biology 2
Partners
CD109CHRDPCPE-1PCPE-2PERIOSTINSIZZLEDTLL1WFIKKN1

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 BMP1 encodes a secreted astacin metalloprotease that cleaves the C-propeptide of procollagens I, II and III (procollagen C-proteinase activity); homozygous null mice lacking the protease active site show aberrant collagen fibril morphology in extracellular matrix and failure of ventral body wall closure, demonstrating in vivo requirement for BMP1 in procollagen processing and collagen fibril formation. Gene knockout (Bmp1 null mice), metabolic labeling, immunofluorescence, electron microscopy Development High 8951074
1999 Among the four mammalian BMP1/TLD-related proteases, BMP1 and mTLL-1 (but not mTLD or mTLL-2) cleave Chordin at sites similar to procollagen C-propeptide cleavage sites, thereby counteracting the dorsalizing activity of Chordin and activating BMP2/4 signaling; BMP1 and mTLL-1 also process procollagen C-propeptides, while mTLL-2 lacks this activity. In vitro cleavage assays, overexpression in Xenopus embryos (functional rescue/dorsalization assays) Developmental biology High 10479448
2003 BMP1 (encoded by Bmp1) and mammalian Tolloid-like 1 (mTLL-1, encoded by Tll1) are together responsible for in vivo cleavage of Chordin in mammals, and mTLL-1 provides residual procollagen C-proteinase activity observed in Bmp1−/− embryos, as demonstrated by removal of functional redundancy in doubly null mouse embryos. Double Bmp1/Tll1 knockout mouse embryos, biochemical analysis, proteomics Molecular and cellular biology High 12808086
2003 BMP1 activates latent myostatin by cleaving the myostatin propeptide within the latent myostatin complex (noncovalent complex of propeptide and C-terminal dimer); a propeptide mutant resistant to BMP1/TLD cleavage caused significant increases in muscle mass when injected into adult mice, confirming in vivo relevance. In vitro cleavage assay, propeptide mutagenesis, in vivo injection into adult mice Proceedings of the National Academy of Sciences of the United States of America High 14671324
2003 The minimal domain structure required for BMP1 procollagen C-proteinase (PCP) activity comprises the metalloproteinase domain plus CUB1 and CUB2 domains; the EGF-like and CUB3 domains are dispensable for PCP activity; Glu-483 on the β4-β5 loop of CUB2 is essential for C-proteinase activity; CUB1 and its location adjacent to the metalloproteinase domain are required for secretion. Domain deletion/swap mutagenesis, in vitro procollagen cleavage assays, secretion assays The Journal of biological chemistry High 12637537
2003 The prodomain of BMP1 is cleaved by furin-like/paired basic proprotein convertases in the trans-Golgi network (TGN), activating BMP1; inhibition of furin results in secretion of inactive pro-BMP1 unable to cleave procollagen; site-directed mutagenesis of the RSRR cleavage site to RSAA confirmed this site but showed prodomain cleavage is not required for secretion; BMP1 localizes to the TGN and plasma membrane. Furin inhibitor treatment, recombinant furin cleavage assay, site-directed mutagenesis, peptide N-glycosidase/neuraminidase digestion, immunofluorescence The Journal of biological chemistry High 12637537 12637569
2003 The prodomain of BMP1 is cleaved by furin-like/paired basic proprotein convertases in the trans-Golgi network, activating the proteinase; BMP1 first appears in the TGN during sialylation. Furin inhibitor treatment, recombinant furin cleavage, mutagenesis of RSRR prodomain cleavage site, glycosidase digestion, immunofluorescence localization The Journal of biological chemistry High 12637569
2004 BMP1/Tolloid-like metalloproteinases cleave endorepellin (the angiostatic C-terminal fragment of perlecan) at the physiologically relevant site to release the LG3 domain from recombinant endorepellin and from endogenous perlecan in cultured cells; LG3 anti-angiogenic activity requires specific amino acids involved in Ca2+ coordination. In vitro cleavage assay with recombinant endorepellin, cell culture processing assays, site-directed mutagenesis, angiogenic assays, molecular modeling The Journal of biological chemistry High 15591058
2005 PCPE-1 specifically enhances BMP1-mediated C-terminal processing of fibrillar procollagens (I and III) but has no effect on BMP1 processing of procollagen VII, procollagen V N-propeptide, laminin 5 γ2 chain, osteoglycin, prolysyl oxidase, or chordin; PCPE-1 enhancement requires the native disulfide-bonded conformation of procollagen and recognition sites in both the C-propeptide and C-telopeptide regions. In vitro BMP1 cleavage assays with multiple substrates, procollagen conformational variants The Journal of biological chemistry High 15834133
2005 The minimal domain structure for BMP1 chordinase activity comprises the metalloproteinase domain (from BMP1 or mTLL-2) plus the CUB1 domain specifically of BMP1 (CUB1 of mTLL-2 cannot substitute); the metalloproteinase and CUB2 domains are absolutely required for PCP activity; PCPE-1 does not enhance BMP1 cleavage of chordin. Domain swap mutagenesis between BMP1 and mTLL-2, in vitro chordin and procollagen cleavage assays The Journal of biological chemistry High 15817489
2006 BMP1 cleaves LTBP1 at two specific sites, liberating the large latent TGFβ1 complex from the ECM; consequent TGFβ1 activation occurs via cleavage of LAP by non-BMP1-like proteinases (predominantly MMP2-dependent in mouse embryo fibroblasts); TGFβ1 induces BMP1 expression, completing a feed-forward loop in tissue remodeling. In vitro cleavage assay, mouse embryo fibroblast culture, in vivo evidence, MMP2 inhibitor/genetic experiments The Journal of cell biology High 17015622
2007 BMP1 cleaves human proapolipoprotein A1 (pro-apoA1) and is the major or only apoA1-converting proteinase secreted by HepG2 and CHO cells; BMP1 stimulates conversion of newly secreted pro-apoA1 to its phospholipid-binding form, promoting functional HDL formation; α2-macroglobulin inhibits BMP1-mediated pro-apoA1 maturation. Recombinant BMP1 cleavage assay, BMP1 antibody and siRNA knockdown in HepG2 and CHO cells Biochemistry Medium 17580958
2007 The non-catalytic CUB and EGF domains of BMP1 confer substrate selectivity; the isolated protease domain alone lacks substrate specificity and degrades fibronectin, collagen I, collagen IV (left intact by full-length BMP1), and completely degrades procollagen VII rather than stopping at the physiological cleavage site. Comparison of recombinant full-length BMP1 vs. isolated protease domain, in vitro cleavage assays with multiple substrates Biological chemistry Medium 17516847
2009 Three isoforms of BMP1 (classic BMP1, mTLD/BMP1-3, and BMP1-5) cleave the propeptide from decorin (and probiglycan), yielding mature proteoglycan; propeptide removal is not required for addition of the glycosaminoglycan chain. In vitro cleavage assays with recombinant substrates and three BMP1 isoforms, cell culture processing Biochemical and biophysical research communications Medium 20026052
2010 Periostin promotes BMP1-mediated proteolytic activation of lysyl oxidase (LOX) by interacting with BMP1 (co-immunoprecipitation and solid-phase binding assays), enhancing BMP1 deposition on the extracellular matrix and thus increasing cleavage of the LOX propeptide; periostin-null mice show reduced active LOX in calvarial osteoblasts. Co-immunoprecipitation, solid-phase binding assay, periostin-null mouse osteoblasts, overexpression The Journal of biological chemistry High 20181949
2010 Three isoforms of BMP1 (BMP1, mTLD, BMP1-5) cleave recombinant DSPP at the MQGDD motif to generate DSP and DPP; mutation of MQGDD to IEGDD abolished cleavage by all isoforms; neither PCPE-1 nor sFRP2 enhanced BMP1 cleavage of DSPP or DMP1. In vitro cleavage assays with recombinant substrates and three BMP1 isoforms, mutagenesis of cleavage motif, cell-based processing in bone marrow stromal cells Matrix biology High 20079836
2011 A homozygous missense mutation Phe249Leu in the BMP1 protease domain causes deficient BMP1/mTLD proteolytic activity on the procollagen I C-terminal propeptide (PICP); overexpression of mutant mTLD in fibroblasts failed to enhance proα1(I) C-terminal processing, confirming loss-of-function; this establishes BMP1 mutation as a cause of autosomal recessive osteogenesis imperfecta. Patient fibroblast cell culture (procollagen processing analysis), overexpression of wild-type vs. mutant mTLD in NIH3T3 and primary fibroblasts, homozygosity mapping Human mutation High 22052668
2012 BMP1 is critically required for mature collagen generation in bone, downstream of osteoblast maturation; attenuated BMP1 function due to a c.34G>C mutation impairs secretion and alters posttranslational modification, leading to increased bone mineral density and recurrent fractures; zebrafish bmp1a mutants show conservation of this function in osteogenesis. Whole-exome sequencing, biochemical secretion assays, zebrafish genetic mutant analysis, histological and biochemical bone analyses American journal of human genetics High 22482805
2014 Postnatal simultaneous ablation of Bmp1 and Tll1 in mice produces osteogenesis imperfecta with spontaneous fractures, osteomalacia, thinned/porous cortical bone, reduced procollagen and DMP1 processing, high bone turnover, defective osteocyte maturation with decreased sclerostin expression, and marked induction of canonical Wnt signaling. Conditional double knockout mice (floxed Bmp1 and Tll1), skeletal phenotyping, histomorphometry, biochemical processing assays, gene expression analysis Human molecular genetics High 24419319
2014 BMP1 directly cleaves the TGF-β co-receptors betaglycan and CD109, altering their ability to interact with TGF-β and leading to increased and prolonged SMAD2 phosphorylation in BMP1-overexpressing cells; betaglycan processing was confirmed in primary corneal keratocytes. iTRAQ quantitative proteomics, direct in vitro cleavage assays, mass spectrometry cleavage site mapping, SMAD2 phosphorylation assays, primary cell validation Cellular and molecular life sciences High 25260970
2015 BMP1/mTLD deficiency in humans (biallelic BMP1 mutations) causes defective C-propeptide cleavage of fibrillar procollagens I–III and impairs processing of small leucine-rich proteoglycan prodecorin, resulting in impaired heterotypic type I/V collagen fibril assembly in the ECM. Patient fibroblast processing assays, immunofluorescence staining of collagen types I and V, transmission electron microscopy of dermis Journal of bone and mineral research High 25656619
2016 Loss of BMP1-like proteinase activity in skin (BTKO mice) results in markedly thinned and fragile skin with densely packed collagen fibrils and delayed wound healing, with deficits in processing of collagens I and III, decorin, biglycan, and laminin 332; notably, collagen VII processing was not affected, indicating it is processed by non-BMP1-like proteinases. Conditional double Bmp1/Tll1 knockout mice (BTKO), histology, electron microscopy, wound healing assays, biochemical processing assays Matrix biology High 27363389
2016 Full-length human BMP1 contains a rare vicinal disulfide linkage (C185-C186) in the catalytic domain confirmed by mass spectrometry; three N-glycosylation sites (N142, N363, N599), an O-glycosylation site, and an Asn-hydroxylation in the EGF domain are present as post-translational modifications. High-mass-accuracy LC-MS/MS on full-length BMP1 from mammalian cells, enzymatic digestion under native conditions Journal of proteomics Medium 26944735
2019 BMP1 cleaves the LOX precursor to activate LOX; ADAMTS2 and ADAMTS14 also cleave the LOX precursor at a site 50 amino acids downstream of the BMP1 cleavage site (between Asp-218 and Tyr-219); the region between BMP1 and ADAMTS cleavage sites contains tyrosine O-sulfation sites that contribute to LOX binding to collagen, providing a mechanism for differential regulation of LOX-collagen interaction. Murine skin fibroblasts and HEK293 cell models, immunoprecipitation, LOX enzymatic activity assays, solid-phase binding assays, proteomics The Journal of biological chemistry High 31152061
2019 BMP1 cleaves the collagen VI α3 chain to release endotrophin (C5 domain)-containing fragments; the exact BMP1 cleavage site was determined by biochemical and isotopic MS-based analyses; furin-like proprotein convertases release a large C2-C5 fragment; these proteolytic maturations occur after secretion of collagen VI tetramers, during microfibril assembly. Biochemical cleavage assays, isotopic MS-based analyses, immunofluorescence microscopy, electron microscopy The Journal of biological chemistry High 31346034
2020 BMP1 cleaves thrombospondin-1 (TSP-1) between the VWFC/procollagen-like domain and the type 1 repeats; this cleavage releases TSP-1 C-terminal domains from the ECM, abolishes TSP-1 cooperative interactions with heparan sulfate proteoglycans and CD36, disrupts cell adhesion, and potentiates TSP-1-mediated activation of latent TGF-β via the canonical SMAD pathway; endogenous BMP1 cleaves TSP-1 in corneal keratocytes. BMP1 overexpression in HT1080 and 293-EBNA cells, primary corneal keratocyte experiments, SMAD pathway reporter assays, cell adhesion assays, ECM fractionation Science signaling High 32636307
2020 Genetic ablation of Bmp1 in primary murine lung fibroblasts abrogates COOH-terminal cleavage of type I procollagen (CICP production); BMP1 siRNA knockdown or small-molecule inhibitor in human lung fibroblasts reduces the majority of CICP production and collagen deposition; BMP1 acts extracellularly as the major nonredundant proteinase for procollagen C-terminal processing in lung fibroblasts. Bmp1 genetic KO in primary murine lung fibroblasts, siRNA knockdown and small-molecule inhibitor in human lung fibroblasts, antibody inhibitor characterization, lung organoid cultures, CICP ELISA American journal of physiology. Cell physiology High 33206546
2022 BMP1 deletion alone (Bmp1 cKO) does not protect mice from bleomycin-induced lung fibrosis, and Bmp1 deletion has no significant impact on CICP production in fibrotic mouse lungs, indicating that BMP1 is not required for lung fibrosis in the bleomycin mouse model (negative finding for BMP1 in lung fibrosis). Inducible Bmp1 conditional knockout mice, bleomycin lung fibrosis model, CICP measurement Scientific reports Medium 35361882
2022 BMP1 cleaves LOXL1 at a unique site within the pro-peptide region; ADAMTS14 processes LOXL1 at three different sites within the pro-peptide and at the first residues of the catalytic domain; differential cleavage by these proteases may generate LOXL1 forms with different functional capabilities. Genetic cellular models (knockdown/overexpression), proteomic analyses to identify cleavage sites International journal of molecular sciences Medium 35328709
2023 BMP1 cleaves the low-density lipoprotein receptor (LDLR) within its ligand-binding domain in hepatocytes; among all six astacin proteases expressed in human hepatocytes (including meprins and mammalian tolloid), only BMP1 contributes to LDLR cleavage; the minimum amino acid requirements for mouse LDLR susceptibility to BMP1 cleavage are mutations at the P1' and P2 positions of the cleavage site. Pharmacological inhibition, siRNA/genetic knockdown of individual astacin proteases in hepatocytes, mutagenesis of LDLR cleavage site, LDL-cholesterol internalization assay FEBS letters High 37235726
2023 PCPE-2 is an endogenous specific inhibitor of BMP-1/tolloid-like proteinases; it directly binds BTPs and potently counteracts their proteolytic activities on multiple substrates, acting in opposition to the BTP-enhancing function previously attributed to PCPE-1. Direct binding assays, in vitro protease activity assays on multiple substrates, comparison with PCPE-1 Nature communications High 38049428
2023 O-fucosylation of BMP1 (by poFUT1) promotes BMP1 secretion to the extracellular matrix and enhances BMP1 binding to chordin (CHRD); this interaction releases BMP4 from CHRD and activates the BMP/Smad signaling pathway, promoting decidualization of human endometrial stromal cells. Human endometrial stromal cell culture, O-fucosylation manipulation (poFUT1 overexpression/knockdown), BMP1-CHRD binding assays, Smad signaling readouts, in vivo tissue expression analysis Biology of reproduction Medium 37338142
2002 PCPE-1 binds to the C-propeptide domain of procollagen I/III with nanomolar affinity (Kd ~150-400 nM for isolated C-propeptide; ~1 nM for intact procollagen) in a calcium/manganese-dependent manner; PCPE-1 also binds pN-collagen (procollagen lacking C-propeptide), indicating binding to sites on both sides of the BMP1 cleavage site; the stoichiometry of the PCPE/C-propeptide interaction is 1:1. Surface plasmon resonance (BIAcore), ligand blotting, chemical cross-linking The Journal of biological chemistry Medium 12105202
2012 Sizzled (a secreted frizzled-related protein from Xenopus/zebrafish) is a tight-binding inhibitor of human BMP1 (Ki = 1.5 nM) acting directly on the BMP1 catalytic domain via its frizzled domain; mammalian sFRP-1, -2, and -4 do not inhibit human BMP1 activity on procollagen I, procollagen III, pN-collagen V, or prolysyl oxidase. In vitro BMP1 activity assays with multiple substrates, inhibitor kinetics (Ki determination), domain deletion analysis of sizzled The Journal of biological chemistry High 22825851
2016 WFIKKN1 enhances the rate of BMP1-mediated cleavage of the latent myostatin propeptide; the KKN1 fragment generated by BMP1 cleavage of WFIKKN1 itself contributes most significantly to this enhancer activity, likely by shifting latent myostatin from a closed homodimer to a more open conformation that exposes BMP1 cleavage sites; heparin superstimulates the KKN1 enhancer activity by increasing local concentrations. In vitro cleavage assays, homology modeling, heparin-binding studies The FEBS journal Medium 27782377

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Activation of latent myostatin by the BMP-1/tolloid family of metalloproteinases. Proceedings of the National Academy of Sciences of the United States of America 351 14671324
2010 Interaction between periostin and BMP-1 promotes proteolytic activation of lysyl oxidase. The Journal of biological chemistry 235 20181949
2006 BMP1 controls TGFbeta1 activation via cleavage of latent TGFbeta-binding protein. The Journal of cell biology 222 17015622
1999 Mammalian BMP-1/Tolloid-related metalloproteinases, including novel family member mammalian Tolloid-like 2, have differential enzymatic activities and distributions of expression relevant to patterning and skeletogenesis. Developmental biology 221 10479448
1996 Failure of ventral body wall closure in mouse embryos lacking a procollagen C-proteinase encoded by Bmp1, a mammalian gene related to Drosophila tolloid. Development (Cambridge, England) 184 8951074
2012 Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish. American journal of human genetics 168 22482805
2000 The BMP1 gene is essential for pathogenicity in the gray mold fungus Botrytis cinerea. Molecular plant-microbe interactions : MPMI 156 10875333
2004 BMP-1/Tolloid-like metalloproteases process endorepellin, the angiostatic C-terminal fragment of perlecan. The Journal of biological chemistry 154 15591058
2011 Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta. Human mutation 153 22052668
1992 Early mRNAs, spatially restricted along the animal-vegetal axis of sea urchin embryos, include one encoding a protein related to tolloid and BMP-1. Development (Cambridge, England) 124 1618141
2015 BMP-1/tolloid-like proteinases synchronize matrix assembly with growth factor activation to promote morphogenesis and tissue remodeling. Matrix biology : journal of the International Society for Matrix Biology 119 25701650
2006 Developmental roles of the BMP1/TLD metalloproteinases. Birth defects research. Part C, Embryo today : reviews 116 16622848
1992 Spatial and temporal expression pattern during sea urchin embryogenesis of a gene coding for a protease homologous to the human protein BMP-1 and to the product of the Drosophila dorsal-ventral patterning gene tolloid. Development (Cambridge, England) 107 1339338
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
2013 miR-194 suppresses metastasis of non-small cell lung cancer through regulating expression of BMP1 and p27(kip1). Oncogene 94 23584484
2005 Substrate-specific modulation of a multisubstrate proteinase. C-terminal processing of fibrillar procollagens is the only BMP-1-dependent activity to be enhanced by PCPE-1. The Journal of biological chemistry 93 15834133
2010 Dentin sialophosphoprotein (DSPP) is cleaved into its two natural dentin matrix products by three isoforms of bone morphogenetic protein-1 (BMP1). Matrix biology : journal of the International Society for Matrix Biology 74 20079836
2003 Paired basic/Furin-like proprotein convertase cleavage of Pro-BMP-1 in the trans-Golgi network. The Journal of biological chemistry 74 12637569
1991 Bone morphogenetic protein: chromosomal localization of human genes for BMP1, BMP2A, and BMP3. Genomics 71 2004778
1994 Mutational analysis of the Drosophila tolloid gene, a human BMP-1 homolog. Development (Cambridge, England) 67 7600963
2018 LncRNA NEAT1/miR-29b-3p/BMP1 axis promotes osteogenic differentiation in human bone marrow-derived mesenchymal stem cells. Pathology, research and practice 65 30638953
1994 Characterization of tolloid-related-1: a BMP-1-like product that is required during larval and pupal stages of Drosophila development. Developmental biology 65 7813777
2003 Bone morphogenetic protein-1 (BMP-1). Identification of the minimal domain structure for procollagen C-proteinase activity. The Journal of biological chemistry 62 12637537
1998 BMP1-related metalloproteinases promote the development of ventral mesoderm in early Xenopus embryos. Developmental biology 62 9520331
1997 A developmental gene (Tolloid/BMP-1) is regulated in Aplysia neurons by treatments that induce long-term sensitization. The Journal of neuroscience : the official journal of the Society for Neuroscience 62 8987797
1994 Embryonic expression of mouse bone morphogenetic protein-1 (BMP-1), which is related to the Drosophila dorsoventral gene tolloid and encodes a putative astacin metalloendopeptidase. Developmental biology 62 8174772
2014 Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice. Human molecular genetics 58 24419319
2000 Is chordin a long-range- or short-range-acting factor? Roles for BMP1-related metalloproteases in chordin and BMP4 autofeedback loop regulation. Developmental biology 56 10864466
2011 Bone morphogenetic protein (BMP)1-3 enhances bone repair. Biochemical and biophysical research communications 52 21453682
2011 Expression of Wnt9, TCTP, and Bmp1/Tll in sea cucumber visceral regeneration. Gene expression patterns : GEP 51 22079950
2002 Interaction properties of the procollagen C-proteinase enhancer protein shed light on the mechanism of stimulation of BMP-1. The Journal of biological chemistry 50 12105202
2019 Differential cleavage of lysyl oxidase by the metalloproteinases BMP1 and ADAMTS2/14 regulates collagen binding through a tyrosine sulfate domain. The Journal of biological chemistry 49 31152061
2016 BMP1-like proteinases are essential to the structure and wound healing of skin. Matrix biology : journal of the International Society for Matrix Biology 49 27363389
1996 hch-1, a gene required for normal hatching and normal migration of a neuroblast in C. elegans, encodes a protein related to TOLLOID and BMP-1. The EMBO journal 49 8861940
2006 Sea urchin metalloproteases: a genomic survey of the BMP-1/tolloid-like, MMP and ADAM families. Developmental biology 47 17059814
1995 The tolkin gene is a tolloid/BMP-1 homologue that is essential for Drosophila development. Genetics 47 8536976
1996 BMP-1 and the astacin family of metalloproteinases: a potential link between the extracellular matrix, growth factors and pattern formation. BioEssays : news and reviews in molecular, cellular and developmental biology 46 8787532
2019 C-terminal proteolysis of the collagen VI α3 chain by BMP-1 and proprotein convertase(s) releases endotrophin in fragments of different sizes. The Journal of biological chemistry 45 31346034
2012 Bacillus thuringiensis metalloproteinase Bmp1 functions as a nematicidal virulence factor. Applied and environmental microbiology 45 23124228
2015 The signalling mucin Msb2 regulates surface sensing and host penetration via BMP1 MAP kinase signalling in Botrytis cinerea. Molecular plant pathology 41 25582910
2015 Defective Proteolytic Processing of Fibrillar Procollagens and Prodecorin Due to Biallelic BMP1 Mutations Results in a Severe, Progressive Form of Osteogenesis Imperfecta. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 41 25656619
2007 Bone morphogenetic protein-1 (BMP-1) cleaves human proapolipoprotein A1 and regulates its activation for lipid binding. Biochemistry 39 17580958
2005 Identification of the minimal domain structure of bone morphogenetic protein-1 (BMP-1) for chordinase activity: chordinase activity is not enhanced by procollagen C-proteinase enhancer-1 (PCPE-1). The Journal of biological chemistry 36 15817489
2014 A polyadenylation site variant causes transcript-specific BMP1 deficiency and frequent fractures in children. Human molecular genetics 35 25214535
2020 BMP-1 disrupts cell adhesion and enhances TGF-β activation through cleavage of the matricellular protein thrombospondin-1. Science signaling 33 32636307
2001 Bone morphogenetic protein-1 (BMP-1) mediates C-terminal processing of procollagen V homotrimer. The Journal of biological chemistry 33 11358968
2009 Decorin is processed by three isoforms of bone morphogenetic protein-1 (BMP1). Biochemical and biophysical research communications 31 20026052
2003 BMP-1-mediated proteolytic processing of alternatively spliced isoforms of collagen type XI. The Biochemical journal 30 12962540
2002 Xolloid-related: a novel BMP1/Tolloid-related metalloprotease is expressed during early Xenopus development. Mechanisms of development 30 12464431
2007 The protease domain of procollagen C-proteinase (BMP1) lacks substrate selectivity, which is conferred by non-proteolytic domains. Biological chemistry 29 17516847
1999 Regulation of BMP signaling by the BMP1/TLD-related metalloprotease, SpAN. Developmental biology 29 9918695
2014 Proteolytic control of TGF-β co-receptor activity by BMP-1/tolloid-like proteases revealed by quantitative iTRAQ proteomics. Cellular and molecular life sciences : CMLS 28 25260970
2013 Hyperosteoidosis and hypermineralization in the same bone: bone tissue analyses in a boy with a homozygous BMP1 mutation. Calcified tissue international 28 24091809
2012 Sizzled is unique among secreted frizzled-related proteins for its ability to specifically inhibit bone morphogenetic protein-1 (BMP-1)/tolloid-like proteinases. The Journal of biological chemistry 27 22825851
2022 Lysyl oxidase promotes anaplastic thyroid carcinoma cell proliferation and metastasis mediated via BMP1. Gland surgery 26 35242686
2016 Phenotypic variability in patients with osteogenesis imperfecta caused by BMP1 mutations. American journal of medical genetics. Part A 26 27576954
2014 Report of a newly indentified patient with mutations in BMP1 and underlying pathogenetic aspects. American journal of medical genetics. Part A 26 24648371
2006 bmp1 and mini fin are functionally redundant in regulating formation of the zebrafish dorsoventral axis. Mechanisms of development 26 16824737
2015 Identification and in vivo functional characterization of novel compound heterozygous BMP1 variants in osteogenesis imperfecta. Human mutation 25 25402547
2017 BMP1 and TLL1 Are Required for Maintaining Periodontal Homeostasis. Journal of dental research 23 28068493
2000 Cloning of the chick BMP1/Tolloid cDNA and expression in skeletal tissues. Gene 23 10806368
2024 Activated hepatic stellate cell-derived Bmp-1 induces liver fibrosis via mediating hepatocyte epithelial-mesenchymal transition. Cell death & disease 21 38216590
2023 Functionally distinct BMP1 isoforms show an opposite pattern of abundance in plasma from non-small cell lung cancer subjects and controls. PloS one 21 36989217
2018 Inhibitors of BMP-1/tolloid-like proteinases: efficacy, selectivity and cellular toxicity. FEBS open bio 20 30524951
2019 BMP1 inhibitor UK383,367 attenuates renal fibrosis and inflammation in CKD. American journal of physiology. Renal physiology 19 31545926
2012 Zebrafish scube1 (signal peptide-CUB (complement protein C1r/C1s, Uegf, and Bmp1)-EGF (epidermal growth factor) domain-containing protein 1) is involved in primitive hematopoiesis. The Journal of biological chemistry 19 23271740
2010 Apoptogenic activity and toxicity studies of a cytotoxic protein (BMP1) from the aqueous extract of common Indian toad (Bufo melanostictus Schneider) skin. Toxicon : official journal of the International Society on Toxinology 19 21144856
2001 Mutational analysis of the BMP-1 gene in patients with gastroschisis. Journal of pediatric surgery 19 11381418
2018 Systemic inhibition of BMP1-3 decreases progression of CCl4-induced liver fibrosis in rats. Growth factors (Chur, Switzerland) 17 29482391
2018 Novel mutations in BMP1 induce a rare type of osteogenesis imperfecta. Clinica chimica acta; international journal of clinical chemistry 17 30408480
2017 Opposing Roles of Epidermal Integrins α3β1 and α9β1 in Regulation of mTLD/BMP-1-Mediated Laminin-γ2 Processing during Wound Healing. The Journal of investigative dermatology 17 28923241
2020 Extracellular BMP1 is the major proteinase for COOH-terminal proteolysis of type I procollagen in lung fibroblasts. American journal of physiology. Cell physiology 16 33206546
2015 BMP-1 participates in the selection and dominance of buffalo follicles by regulating the proliferation and apoptosis of granulosa cells. Theriogenology 16 26778140
2011 Anticancer activity of a low immunogenic protein toxin (BMP1) from Indian toad (Bufo melanostictus, Schneider) skin extract. Toxicon : official journal of the International Society on Toxinology 16 21635912
2017 Two novel compound heterozygous BMP1 mutations in a patient with osteogenesis imperfecta: a case report. BMC medical genetics 15 28257626
2016 Characterization of post-translational modifications in full-length human BMP-1 confirms the presence of a rare vicinal disulfide linkage in the catalytic domain and highlights novel features of the EGF domain. Journal of proteomics 14 26944735
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
2002 Isolation of connective-tissue-specific genes involved in Xenopus intestinal remodeling: thyroid hormone up-regulates Tolloid/BMP-1 expression. Development genes and evolution 13 12203091
2023 Knockdown of Bmp1 and Pls1 Virulence Genes by Exogenous Application of RNAi-Inducing dsRNA in Botrytis cinerea. International journal of molecular sciences 12 36902297
2015 CCN2/CTGF expression via cellular uptake of BMP-1 is associated with reparative dentinogenesis. Oral diseases 12 25944709
2024 BMP1 Promotes Keloid by Inducing Fibroblast Inflammation and Fibrogenesis. Journal of cellular biochemistry 11 38860429
2021 Epidermal Integrin α3β1 Regulates Tumor-Derived Proteases BMP-1, Matrix Metalloprotease-9, and Matrix Metalloprotease-3. JID innovations : skin science from molecules to population health 11 34909716
2017 Interaction of Complement Defence Collagens C1q and Mannose-Binding Lectin with BMP-1/Tolloid-like Proteinases. Scientific reports 11 29209066
2014 The diagnostic role of signal peptide-C1r/C1s, Uegf, and Bmp1-epidermal growth factor domain-containing protein 1 in non-ST-elevation acute coronary syndrome. The American journal of emergency medicine 11 25445868
2000 Expression of chick BMP-1/Tolloid during patterning of the neural tube and somites. Mechanisms of development 11 10704876
1993 Mapping of the bone morphogenetic protein 1 gene (BMP1) to 8p21: removal of BMP1 from candidacy for the bone disorder in Langer-Giedion syndrome. Cytogenetics and cell genetics 11 8404039
2023 Identification of PCPE-2 as the endogenous specific inhibitor of human BMP-1/tolloid-like proteinases. Nature communications 10 38049428
2021 LncRNA Bmp1 promotes the healing of intestinal mucosal lesions via the miR-128-3p/PHF6/PI3K/AKT pathway. Cell death & disease 10 34108447
2016 The diagnostic significance of signal peptide-complement C1r/C1s, Uegf, and Bmp1-epidermal growth factor domain-containing protein-1 levels in pulmonary embolism. Annals of thoracic medicine 10 27803754
2022 Cleavage of LOXL1 by BMP1 and ADAMTS14 Proteases Suggests a Role for Proteolytic Processing in the Regulation of LOXL1 Function. International journal of molecular sciences 9 35328709
2022 BMP1 is not required for lung fibrosis in mice. Scientific reports 9 35361882
2018 Synergistic effect of PCPE1 and sFRP2 on the processing of procollagens via BMP1. FEBS letters 9 30411347
2021 A Common Polymorphism in the FADS1 Locus Links miR1908 to Low-Density Lipoprotein Cholesterol Through BMP1. Arteriosclerosis, thrombosis, and vascular biology 7 34134519
2020 Down expression of lnc-BMP1-1 decreases that of Caveolin-1 is associated with the lung cancer susceptibility and cigarette smoking history. Aging 6 31901898
2006 In vivo analysis of the acidic ribosomal proteins BmP1 and BmP2 of the silkworm Bombyx mori in the yeast Saccharomyces cerevisiae. Gene 6 17134850
2023 Proteolysis of the low-density lipoprotein receptor in hepatocytes is mediated by BMP1 but not by other astacin proteases. FEBS letters 5 37235726
2023 O-Fucosylation of BMP1 promotes endometrial decidualization by activating BMP/Smad signaling pathway. Biology of reproduction 5 37338142
2016 Influence of WFIKKN1 on BMP1-mediated activation of latent myostatin. The FEBS journal 5 27782377
2017 Meprin β and BMP-1 are differentially regulated by CaCl2. Cell calcium 4 28365001
2014 Site specificity of DSP-PP cleavage by BMP1. Connective tissue research 4 25158199

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