{"gene":"BMP1","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":1996,"finding":"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.","method":"Gene knockout (Bmp1 null mice), metabolic labeling, immunofluorescence, electron microscopy","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype (aberrant collagen fibrils, failed procollagen processing), replicated across multiple analyses in the same study and corroborated by subsequent literature","pmids":["8951074"],"is_preprint":false},{"year":1999,"finding":"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.","method":"In vitro cleavage assays, overexpression in Xenopus embryos (functional rescue/dorsalization assays)","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro enzymatic assays combined with in vivo Xenopus functional assays; findings replicated across the four family members with distinct results","pmids":["10479448"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Double Bmp1/Tll1 knockout mouse embryos, biochemical analysis, proteomics","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via doubly null mice removing redundancy, combined with biochemical and proteomics validation","pmids":["12808086"],"is_preprint":false},{"year":2003,"finding":"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.","method":"In vitro cleavage assay, propeptide mutagenesis, in vivo injection into adult mice","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro cleavage assay with mutagenesis plus in vivo functional validation","pmids":["14671324"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Domain deletion/swap mutagenesis, in vitro procollagen cleavage assays, secretion assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution with structure-function mutagenesis defining minimal active domain, single lab but multiple mutants tested","pmids":["12637537"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Furin inhibitor treatment, recombinant furin cleavage assay, site-directed mutagenesis, peptide N-glycosidase/neuraminidase digestion, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstitution with recombinant furin, mutagenesis of cleavage site, multiple orthogonal methods in single study","pmids":["12637537","12637569"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Furin inhibitor treatment, recombinant furin cleavage, mutagenesis of RSRR prodomain cleavage site, glycosidase digestion, immunofluorescence localization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (inhibitor, recombinant enzyme, mutagenesis, localization) in a single focused study","pmids":["12637569"],"is_preprint":false},{"year":2004,"finding":"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.","method":"In vitro cleavage assay with recombinant endorepellin, cell culture processing assays, site-directed mutagenesis, angiogenic assays, molecular modeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstitution plus cell-based validation and mutagenesis in one study","pmids":["15591058"],"is_preprint":false},{"year":2005,"finding":"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.","method":"In vitro BMP1 cleavage assays with multiple substrates, procollagen conformational variants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic in vitro reconstitution across multiple substrates with structural substrate variants, single lab","pmids":["15834133"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Domain swap mutagenesis between BMP1 and mTLL-2, in vitro chordin and procollagen cleavage assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — domain swap reconstitution with multiple mutants defining minimal activity domains, single lab","pmids":["15817489"],"is_preprint":false},{"year":2006,"finding":"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.","method":"In vitro cleavage assay, mouse embryo fibroblast culture, in vivo evidence, MMP2 inhibitor/genetic experiments","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro and in vivo evidence combined, multiple orthogonal approaches, identification of specific cleavage sites","pmids":["17015622"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Recombinant BMP1 cleavage assay, BMP1 antibody and siRNA knockdown in HepG2 and CHO cells","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal validation with recombinant enzyme, antibody, and siRNA knockdown in two cell lines, single lab","pmids":["17580958"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Comparison of recombinant full-length BMP1 vs. isolated protease domain, in vitro cleavage assays with multiple substrates","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution comparing two forms on multiple substrates, single lab, no mutagenesis of individual residues","pmids":["17516847"],"is_preprint":false},{"year":2009,"finding":"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.","method":"In vitro cleavage assays with recombinant substrates and three BMP1 isoforms, cell culture processing","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with multiple isoforms and substrates, single lab","pmids":["20026052"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Co-immunoprecipitation, solid-phase binding assay, periostin-null mouse osteoblasts, overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays plus in vivo null mouse validation, multiple orthogonal methods","pmids":["20181949"],"is_preprint":false},{"year":2010,"finding":"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.","method":"In vitro cleavage assays with recombinant substrates and three BMP1 isoforms, mutagenesis of cleavage motif, cell-based processing in bone marrow stromal cells","journal":"Matrix biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis confirming cleavage site, validated in cells, single lab","pmids":["20079836"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Patient fibroblast cell culture (procollagen processing analysis), overexpression of wild-type vs. mutant mTLD in NIH3T3 and primary fibroblasts, homozygosity mapping","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-based functional assay comparing WT and mutant protein with defined biochemical readout, validated in two cell types","pmids":["22052668"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Whole-exome sequencing, biochemical secretion assays, zebrafish genetic mutant analysis, histological and biochemical bone analyses","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetic mutation combined with zebrafish loss-of-function and biochemical validation, multiple orthogonal approaches","pmids":["22482805"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Conditional double knockout mice (floxed Bmp1 and Tll1), skeletal phenotyping, histomorphometry, biochemical processing assays, gene expression analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional double KO with multiple defined cellular/molecular phenotypic readouts","pmids":["24419319"],"is_preprint":false},{"year":2014,"finding":"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.","method":"iTRAQ quantitative proteomics, direct in vitro cleavage assays, mass spectrometry cleavage site mapping, SMAD2 phosphorylation assays, primary cell validation","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — quantitative proteomics discovery followed by direct enzymatic validation with MS site mapping and cell signaling readout, validated in primary cells","pmids":["25260970"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Patient fibroblast processing assays, immunofluorescence staining of collagen types I and V, transmission electron microscopy of dermis","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-based processing assays combined with ultrastructural EM and immunofluorescence, multiple substrates validated","pmids":["25656619"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Conditional double Bmp1/Tll1 knockout mice (BTKO), histology, electron microscopy, wound healing assays, biochemical processing assays","journal":"Matrix biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple orthogonal substrate and phenotypic readouts; negative result on collagen VII is mechanistically informative","pmids":["27363389"],"is_preprint":false},{"year":2016,"finding":"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.","method":"High-mass-accuracy LC-MS/MS on full-length BMP1 from mammalian cells, enzymatic digestion under native conditions","journal":"Journal of proteomics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mass spectrometry PTM characterization with native conditions, single lab, no functional mutagenesis of the PTMs","pmids":["26944735"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Murine skin fibroblasts and HEK293 cell models, immunoprecipitation, LOX enzymatic activity assays, solid-phase binding assays, proteomics","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including enzymatic assay, binding assay, proteomics, and cellular models in one study","pmids":["31152061"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Biochemical cleavage assays, isotopic MS-based analyses, immunofluorescence microscopy, electron microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstitution with MS-based site identification, structural validation by EM and immunofluorescence, single lab","pmids":["31346034"],"is_preprint":false},{"year":2020,"finding":"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.","method":"BMP1 overexpression in HT1080 and 293-EBNA cells, primary corneal keratocyte experiments, SMAD pathway reporter assays, cell adhesion assays, ECM fractionation","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional readouts (adhesion, signaling, ECM fractionation) in multiple cell systems including primary cells","pmids":["32636307"],"is_preprint":false},{"year":2020,"finding":"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.","method":"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","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO combined with siRNA, pharmacological inhibition, and antibody inhibition, multiple orthogonal approaches in two species","pmids":["33206546"],"is_preprint":false},{"year":2022,"finding":"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).","method":"Inducible Bmp1 conditional knockout mice, bleomycin lung fibrosis model, CICP measurement","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean conditional KO in disease model with defined biochemical readout; single lab, negative result","pmids":["35361882"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Genetic cellular models (knockdown/overexpression), proteomic analyses to identify cleavage sites","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based genetic models with proteomics site identification, single lab","pmids":["35328709"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Pharmacological inhibition, siRNA/genetic knockdown of individual astacin proteases in hepatocytes, mutagenesis of LDLR cleavage site, LDL-cholesterol internalization assay","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — pharmacological inhibition, genetic knockdown, site mutagenesis, and functional LDL uptake assay in combination","pmids":["37235726"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Direct binding assays, in vitro protease activity assays on multiple substrates, comparison with PCPE-1","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct binding and enzymatic inhibition assays across multiple substrates, peer-reviewed study","pmids":["38049428"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Human endometrial stromal cell culture, O-fucosylation manipulation (poFUT1 overexpression/knockdown), BMP1-CHRD binding assays, Smad signaling readouts, in vivo tissue expression analysis","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based functional assays with binding assays and signaling readouts, single lab","pmids":["37338142"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Surface plasmon resonance (BIAcore), ligand blotting, chemical cross-linking","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — surface plasmon resonance with multiple interaction partners, single lab","pmids":["12105202"],"is_preprint":false},{"year":2012,"finding":"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.","method":"In vitro BMP1 activity assays with multiple substrates, inhibitor kinetics (Ki determination), domain deletion analysis of sizzled","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinetic inhibitor characterization with domain dissection on multiple substrates, single lab","pmids":["22825851"],"is_preprint":false},{"year":2016,"finding":"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.","method":"In vitro cleavage assays, homology modeling, heparin-binding studies","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mechanistic modeling, single lab","pmids":["27782377"],"is_preprint":false}],"current_model":"BMP1 is a secreted astacin-family zinc metalloproteinase whose prodomain is removed by furin-like convertases in the trans-Golgi network to generate the active enzyme; it acts extracellularly as the principal procollagen C-proteinase (cleaving C-propeptides of procollagens I–III, V, and XI to drive collagen fibril formation), and also processes a broad range of additional substrates including the LOX and LOXL1 propeptides (activating lysyl oxidase-dependent collagen cross-linking), Chordin (releasing BMP2/4 to control dorsoventral patterning), LTBP1 (liberating latent TGF-β from the ECM for subsequent activation), the myostatin propeptide (activating the muscle-mass inhibitor), decorin/biglycan propeptides, DSPP, DMP1, endorepellin/perlecan (releasing the angiostatic LG3 fragment), thrombospondin-1 (disrupting cell adhesion and potentiating TGF-β signaling), the TGF-β co-receptors betaglycan and CD109 (enhancing SMAD2 signaling), pro-apoA1 (enabling functional HDL formation), LDLR (reducing LDL uptake), and the collagen VI α3 chain (releasing endotrophin); substrate selectivity and catalytic efficiency are governed by the non-catalytic CUB1 and CUB2 domains, while CUB1 is also essential for secretion, and activity is positively regulated by PCPE-1 (specific to fibrillar procollagens) and periostin, and negatively regulated by the endogenous inhibitor PCPE-2 and by sizzled."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1996,"claim":"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","pmids":["8951074"],"confidence":"High","gaps":["Residual procollagen processing in nulls implied additional redundant proteases","Did not define which non-collagen substrates contribute to the body-wall phenotype"]},{"year":1999,"claim":"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","pmids":["10479448"],"confidence":"High","gaps":["In vivo mammalian contribution of each family member to Chordin cleavage not yet resolved"]},{"year":2003,"claim":"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","pmids":["12808086"],"confidence":"High","gaps":["Relative contribution of each protease in specific tissues not quantified"]},{"year":2003,"claim":"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","pmids":["12637537","12637569"],"confidence":"High","gaps":["No high-resolution structure of the proenzyme or CUB-substrate interface","Functional role of individual PTMs untested"]},{"year":2003,"claim":"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","pmids":["14671324"],"confidence":"High","gaps":["Physiological setting and tissue context of endogenous myostatin activation by BMP1 not defined"]},{"year":2004,"claim":"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","pmids":["15591058"],"confidence":"High","gaps":["In vivo requirement for BMP1 in LG3 generation and angiogenesis not established"]},{"year":2005,"claim":"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","pmids":["15834133","15817489"],"confidence":"High","gaps":["Structural basis of CUB1-conferred Chordin specificity not solved"]},{"year":2006,"claim":"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","pmids":["17015622"],"confidence":"High","gaps":["BMP1 liberates the latent complex but does not directly activate TGF-β; downstream activation depends on other proteases"]},{"year":2007,"claim":"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","pmids":["17516847","17580958"],"confidence":"Medium","gaps":["pro-apoA1 work from single lab, in vivo HDL relevance untested","No residue-level mapping of CUB selectivity contacts"]},{"year":2010,"claim":"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","pmids":["20181949","20079836"],"confidence":"High","gaps":["Mechanism of periostin-mediated ECM deposition of BMP1 only partially defined"]},{"year":2011,"claim":"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","pmids":["22052668"],"confidence":"High","gaps":["Genotype-phenotype range across BMP1 mutations not fully defined at this stage"]},{"year":2012,"claim":"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","pmids":["22482805"],"confidence":"High","gaps":["Mechanism linking impaired secretion to increased bone mineral density not fully resolved"]},{"year":2014,"claim":"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","pmids":["24419319","25260970"],"confidence":"High","gaps":["Mechanism linking BMP1 loss to canonical Wnt induction in bone not established","Net signaling outcome of co-receptor cleavage may be context-dependent"]},{"year":2015,"claim":"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","pmids":["25656619"],"confidence":"High","gaps":["Quantitative contribution of decorin defect vs. collagen defect to the phenotype unresolved"]},{"year":2016,"claim":"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","pmids":["27363389","26944735","27782377"],"confidence":"High","gaps":["Functional role of identified PTMs untested by mutagenesis","Collagen VII processing attributed to non-BMP1 proteases"]},{"year":2019,"claim":"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","pmids":["31152061","31346034"],"confidence":"High","gaps":["Physiological balance between BMP1 and ADAMTS cleavage of LOX/LOXL1 in vivo unclear"]},{"year":2020,"claim":"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","pmids":["33206546","32636307"],"confidence":"High","gaps":["Tissue specificity of BMP1 nonredundancy vs. mTLL-1 not generalized beyond lung fibroblasts"]},{"year":2022,"claim":"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","pmids":["35361882","35328709"],"confidence":"Medium","gaps":["Negative fibrosis result from single lab/model; redundancy with mTLL-1 may mask requirement","Functional consequences of distinct LOXL1 cleavage products not defined"]},{"year":2023,"claim":"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","pmids":["37235726","38049428","37338142"],"confidence":"High","gaps":["In vivo cholesterol/HDL phenotypes of BMP1-mediated LDLR cleavage untested","O-fucosylation findings from single lab"]},{"year":null,"claim":"How BMP1's CUB domains and cofactors structurally select among its many substrates, and what determines tissue-specific nonredundancy versus mTLL-1, remain unresolved.","evidence":"No high-resolution structure of full-length BMP1 or substrate/cofactor complexes in the corpus","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,3,7,10,19,23,24,25,29]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,4,5]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,5,10,21]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,10,14,25]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[5,6]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,8,20,21,23]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,31]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,19,25,31]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,6,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16,17,18,20]}],"complexes":[],"partners":["TLL1","PCPE-1","PCPE-2","PERIOSTIN","CHRD","WFIKKN1","SIZZLED","CD109"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P13497","full_name":"Bone morphogenetic protein 1","aliases":["Mammalian tolloid protein","mTld","Procollagen C-proteinase","PCP"],"length_aa":986,"mass_kda":111.2,"function":"Metalloprotease that plays key roles in regulating the formation of the extracellular matrix (ECM) via processing of various precursor proteins into mature functional enzymes or structural proteins (PubMed:33206546). Thereby participates in several developmental and physiological processes such as cartilage and bone formation, muscle growth and homeostasis, wound healing and tissue repair (PubMed:32636307, PubMed:33169406). Roles in ECM formation include cleavage of the C-terminal propeptides from procollagens such as procollagen I, II and III or the proteolytic activation of the enzyme lysyl oxidase LOX, necessary to formation of covalent cross-links in collagen and elastic fibers (PubMed:31152061, PubMed:33206546). Additional substrates include matricellular thrombospondin-1/THBS1 whose cleavage leads to cell adhesion disruption and TGF-beta activation (PubMed:32636307) Plays an important role in bone repair by acting as a coactivator of BMP7","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P13497/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BMP1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/BMP1","total_profiled":1310},"omim":[{"mim_id":"614856","title":"OSTEOGENESIS IMPERFECTA, TYPE XIII; OI13","url":"https://www.omim.org/entry/614856"},{"mim_id":"612769","title":"NONCODING NUCLEAR-ENRICHED ABUNDANT TRANSCRIPT 1; NEAT1","url":"https://www.omim.org/entry/612769"},{"mim_id":"610783","title":"MICRO RNA 29B1; MIR29B1","url":"https://www.omim.org/entry/610783"},{"mim_id":"610684","title":"C-TERMINAL DOMAIN NUCLEAR ENVELOPE PHOSPHATASE 1; CTDNEP1","url":"https://www.omim.org/entry/610684"},{"mim_id":"609777","title":"XIN ACTIN-BINDING REPEAT-CONTAINING PROTEIN 1; XIRP1","url":"https://www.omim.org/entry/609777"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/BMP1"},"hgnc":{"alias_symbol":["BMP-1"],"prev_symbol":["PCOLC"]},"alphafold":{"accession":"P13497","domains":[{"cath_id":"3.40.390.10","chopping":"123-317","consensus_level":"high","plddt":88.2638,"start":123,"end":317},{"cath_id":"2.60.120.290","chopping":"321-435","consensus_level":"high","plddt":91.3509,"start":321,"end":435},{"cath_id":"2.60.120.290","chopping":"442-549","consensus_level":"high","plddt":91.7831,"start":442,"end":549},{"cath_id":"2.10.25.10","chopping":"555-589","consensus_level":"medium","plddt":81.5331,"start":555,"end":589},{"cath_id":"2.60.120.290","chopping":"592-705","consensus_level":"high","plddt":88.8932,"start":592,"end":705},{"cath_id":"2.10.25.10","chopping":"711-745","consensus_level":"medium","plddt":74.3917,"start":711,"end":745},{"cath_id":"2.60.120.290","chopping":"749-860","consensus_level":"high","plddt":90.6524,"start":749,"end":860},{"cath_id":"2.60.120.290","chopping":"863-978","consensus_level":"high","plddt":89.2856,"start":863,"end":978}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P13497","model_url":"https://alphafold.ebi.ac.uk/files/AF-P13497-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P13497-F1-predicted_aligned_error_v6.png","plddt_mean":81.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BMP1","jax_strain_url":"https://www.jax.org/strain/search?query=BMP1"},"sequence":{"accession":"P13497","fasta_url":"https://rest.uniprot.org/uniprotkb/P13497.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P13497/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P13497"}},"corpus_meta":[{"pmid":"14671324","id":"PMC_14671324","title":"Activation 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in vivo requirement for BMP1 in procollagen processing and collagen fibril formation.\",\n      \"method\": \"Gene knockout (Bmp1 null mice), metabolic labeling, immunofluorescence, electron microscopy\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype (aberrant collagen fibrils, failed procollagen processing), replicated across multiple analyses in the same study and corroborated by subsequent literature\",\n      \"pmids\": [\"8951074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro cleavage assays, overexpression in Xenopus embryos (functional rescue/dorsalization assays)\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro enzymatic assays combined with in vivo Xenopus functional assays; findings replicated across the four family members with distinct results\",\n      \"pmids\": [\"10479448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Double Bmp1/Tll1 knockout mouse embryos, biochemical analysis, proteomics\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via doubly null mice removing redundancy, combined with biochemical and proteomics validation\",\n      \"pmids\": [\"12808086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro cleavage assay, propeptide mutagenesis, in vivo injection into adult mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro cleavage assay with mutagenesis plus in vivo functional validation\",\n      \"pmids\": [\"14671324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Domain deletion/swap mutagenesis, in vitro procollagen cleavage assays, secretion assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution with structure-function mutagenesis defining minimal active domain, single lab but multiple mutants tested\",\n      \"pmids\": [\"12637537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Furin inhibitor treatment, recombinant furin cleavage assay, site-directed mutagenesis, peptide N-glycosidase/neuraminidase digestion, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstitution with recombinant furin, mutagenesis of cleavage site, multiple orthogonal methods in single study\",\n      \"pmids\": [\"12637537\", \"12637569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Furin inhibitor treatment, recombinant furin cleavage, mutagenesis of RSRR prodomain cleavage site, glycosidase digestion, immunofluorescence localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (inhibitor, recombinant enzyme, mutagenesis, localization) in a single focused study\",\n      \"pmids\": [\"12637569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro cleavage assay with recombinant endorepellin, cell culture processing assays, site-directed mutagenesis, angiogenic assays, molecular modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstitution plus cell-based validation and mutagenesis in one study\",\n      \"pmids\": [\"15591058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro BMP1 cleavage assays with multiple substrates, procollagen conformational variants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic in vitro reconstitution across multiple substrates with structural substrate variants, single lab\",\n      \"pmids\": [\"15834133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Domain swap mutagenesis between BMP1 and mTLL-2, in vitro chordin and procollagen cleavage assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — domain swap reconstitution with multiple mutants defining minimal activity domains, single lab\",\n      \"pmids\": [\"15817489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro cleavage assay, mouse embryo fibroblast culture, in vivo evidence, MMP2 inhibitor/genetic experiments\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro and in vivo evidence combined, multiple orthogonal approaches, identification of specific cleavage sites\",\n      \"pmids\": [\"17015622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Recombinant BMP1 cleavage assay, BMP1 antibody and siRNA knockdown in HepG2 and CHO cells\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal validation with recombinant enzyme, antibody, and siRNA knockdown in two cell lines, single lab\",\n      \"pmids\": [\"17580958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Comparison of recombinant full-length BMP1 vs. isolated protease domain, in vitro cleavage assays with multiple substrates\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution comparing two forms on multiple substrates, single lab, no mutagenesis of individual residues\",\n      \"pmids\": [\"17516847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro cleavage assays with recombinant substrates and three BMP1 isoforms, cell culture processing\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with multiple isoforms and substrates, single lab\",\n      \"pmids\": [\"20026052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, solid-phase binding assay, periostin-null mouse osteoblasts, overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays plus in vivo null mouse validation, multiple orthogonal methods\",\n      \"pmids\": [\"20181949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro cleavage assays with recombinant substrates and three BMP1 isoforms, mutagenesis of cleavage motif, cell-based processing in bone marrow stromal cells\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis confirming cleavage site, validated in cells, single lab\",\n      \"pmids\": [\"20079836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Patient fibroblast cell culture (procollagen processing analysis), overexpression of wild-type vs. mutant mTLD in NIH3T3 and primary fibroblasts, homozygosity mapping\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based functional assay comparing WT and mutant protein with defined biochemical readout, validated in two cell types\",\n      \"pmids\": [\"22052668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-exome sequencing, biochemical secretion assays, zebrafish genetic mutant analysis, histological and biochemical bone analyses\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetic mutation combined with zebrafish loss-of-function and biochemical validation, multiple orthogonal approaches\",\n      \"pmids\": [\"22482805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional double knockout mice (floxed Bmp1 and Tll1), skeletal phenotyping, histomorphometry, biochemical processing assays, gene expression analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional double KO with multiple defined cellular/molecular phenotypic readouts\",\n      \"pmids\": [\"24419319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"iTRAQ quantitative proteomics, direct in vitro cleavage assays, mass spectrometry cleavage site mapping, SMAD2 phosphorylation assays, primary cell validation\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — quantitative proteomics discovery followed by direct enzymatic validation with MS site mapping and cell signaling readout, validated in primary cells\",\n      \"pmids\": [\"25260970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Patient fibroblast processing assays, immunofluorescence staining of collagen types I and V, transmission electron microscopy of dermis\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based processing assays combined with ultrastructural EM and immunofluorescence, multiple substrates validated\",\n      \"pmids\": [\"25656619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional double Bmp1/Tll1 knockout mice (BTKO), histology, electron microscopy, wound healing assays, biochemical processing assays\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple orthogonal substrate and phenotypic readouts; negative result on collagen VII is mechanistically informative\",\n      \"pmids\": [\"27363389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"High-mass-accuracy LC-MS/MS on full-length BMP1 from mammalian cells, enzymatic digestion under native conditions\",\n      \"journal\": \"Journal of proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mass spectrometry PTM characterization with native conditions, single lab, no functional mutagenesis of the PTMs\",\n      \"pmids\": [\"26944735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Murine skin fibroblasts and HEK293 cell models, immunoprecipitation, LOX enzymatic activity assays, solid-phase binding assays, proteomics\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including enzymatic assay, binding assay, proteomics, and cellular models in one study\",\n      \"pmids\": [\"31152061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical cleavage assays, isotopic MS-based analyses, immunofluorescence microscopy, electron microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstitution with MS-based site identification, structural validation by EM and immunofluorescence, single lab\",\n      \"pmids\": [\"31346034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"BMP1 overexpression in HT1080 and 293-EBNA cells, primary corneal keratocyte experiments, SMAD pathway reporter assays, cell adhesion assays, ECM fractionation\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional readouts (adhesion, signaling, ECM fractionation) in multiple cell systems including primary cells\",\n      \"pmids\": [\"32636307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO combined with siRNA, pharmacological inhibition, and antibody inhibition, multiple orthogonal approaches in two species\",\n      \"pmids\": [\"33206546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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).\",\n      \"method\": \"Inducible Bmp1 conditional knockout mice, bleomycin lung fibrosis model, CICP measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO in disease model with defined biochemical readout; single lab, negative result\",\n      \"pmids\": [\"35361882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic cellular models (knockdown/overexpression), proteomic analyses to identify cleavage sites\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based genetic models with proteomics site identification, single lab\",\n      \"pmids\": [\"35328709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Pharmacological inhibition, siRNA/genetic knockdown of individual astacin proteases in hepatocytes, mutagenesis of LDLR cleavage site, LDL-cholesterol internalization assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — pharmacological inhibition, genetic knockdown, site mutagenesis, and functional LDL uptake assay in combination\",\n      \"pmids\": [\"37235726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Direct binding assays, in vitro protease activity assays on multiple substrates, comparison with PCPE-1\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct binding and enzymatic inhibition assays across multiple substrates, peer-reviewed study\",\n      \"pmids\": [\"38049428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Human endometrial stromal cell culture, O-fucosylation manipulation (poFUT1 overexpression/knockdown), BMP1-CHRD binding assays, Smad signaling readouts, in vivo tissue expression analysis\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based functional assays with binding assays and signaling readouts, single lab\",\n      \"pmids\": [\"37338142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Surface plasmon resonance (BIAcore), ligand blotting, chemical cross-linking\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — surface plasmon resonance with multiple interaction partners, single lab\",\n      \"pmids\": [\"12105202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro BMP1 activity assays with multiple substrates, inhibitor kinetics (Ki determination), domain deletion analysis of sizzled\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinetic inhibitor characterization with domain dissection on multiple substrates, single lab\",\n      \"pmids\": [\"22825851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro cleavage assays, homology modeling, heparin-binding studies\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mechanistic modeling, single lab\",\n      \"pmids\": [\"27782377\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BMP1 is a secreted astacin-family zinc metalloproteinase whose prodomain is removed by furin-like convertases in the trans-Golgi network to generate the active enzyme; it acts extracellularly as the principal procollagen C-proteinase (cleaving C-propeptides of procollagens I–III, V, and XI to drive collagen fibril formation), and also processes a broad range of additional substrates including the LOX and LOXL1 propeptides (activating lysyl oxidase-dependent collagen cross-linking), Chordin (releasing BMP2/4 to control dorsoventral patterning), LTBP1 (liberating latent TGF-β from the ECM for subsequent activation), the myostatin propeptide (activating the muscle-mass inhibitor), decorin/biglycan propeptides, DSPP, DMP1, endorepellin/perlecan (releasing the angiostatic LG3 fragment), thrombospondin-1 (disrupting cell adhesion and potentiating TGF-β signaling), the TGF-β co-receptors betaglycan and CD109 (enhancing SMAD2 signaling), pro-apoA1 (enabling functional HDL formation), LDLR (reducing LDL uptake), and the collagen VI α3 chain (releasing endotrophin); substrate selectivity and catalytic efficiency are governed by the non-catalytic CUB1 and CUB2 domains, while CUB1 is also essential for secretion, and activity is positively regulated by PCPE-1 (specific to fibrillar procollagens) and periostin, and negatively regulated by the endogenous inhibitor PCPE-2 and by sizzled.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BMP1 is a secreted astacin-family zinc metalloproteinase that serves as the principal procollagen C-proteinase, cleaving the C-propeptides of fibrillar procollagens I\\u2013III 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 [#0], 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 [#16, #17, #20]. 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 [#5, #6]. Beyond procollagens, BMP1 is a broad-specificity ECM-remodeling protease: it cleaves Chordin to release BMP2/4 and antagonize dorsalizing signals [#1], activates latent myostatin by cleaving its propeptide [#3], processes LTBP1 to liberate latent TGF-\\u03b2 in a TGF-\\u03b2-inducible feed-forward loop [#10], activates lysyl oxidases LOX and LOXL1 by propeptide removal [#23, #28], matures decorin/biglycan and the dentin proteins DSPP/DMP1 [#13, #15], releases the angiostatic LG3 fragment from endorepellin/perlecan [#7] and endotrophin from collagen VI \\u03b13 [#24], and cleaves thrombospondin-1 and the TGF-\\u03b2 co-receptors betaglycan and CD109 to potentiate SMAD2 signaling [#19, #25]. It also acts in lipid metabolism, maturing pro-apoA1 for functional HDL formation and cleaving LDLR to reduce LDL uptake in hepatocytes [#11, #29]. Substrate selectivity and catalytic efficiency are governed by the non-catalytic CUB1 and CUB2 domains\\u2014the isolated protease domain loses specificity and over-digests substrates, while CUB1 is additionally required for secretion and CUB2 (residue Glu-483) for procollagen cleavage [#4, #9, #12]. Activity is positively modulated by PCPE-1 (specific to fibrillar procollagens), periostin, and WFIKKN1, and negatively regulated by PCPE-2, sizzled, and \\u03b12-macroglobulin [#8, #14, #34, #30, #33]. BMP1 functions redundantly with the related protease mTLL-1/TLL1, and combined ablation is required to fully remove procollagen and Chordin processing in vivo [#2, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that BMP1 is the in vivo procollagen C-proteinase whose activity is required for normal collagen fibril formation, defining its core ECM function.\",\n      \"evidence\": \"Bmp1 active-site null mice with metabolic labeling, immunofluorescence, and electron microscopy of ECM\",\n      \"pmids\": [\"8951074\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Residual procollagen processing in nulls implied additional redundant proteases\", \"Did not define which non-collagen substrates contribute to the body-wall phenotype\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro cleavage assays and Xenopus dorsalization/rescue assays across four BMP1/TLD proteases\",\n      \"pmids\": [\"10479448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo mammalian contribution of each family member to Chordin cleavage not yet resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolved the redundancy between BMP1 and mTLL-1, showing both are jointly responsible for Chordin and residual procollagen processing in mammals.\",\n      \"evidence\": \"Bmp1/Tll1 double-knockout mouse embryos with biochemical and proteomic analysis\",\n      \"pmids\": [\"12808086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each protease in specific tissues not quantified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined how BMP1 itself is activated\\u2014prodomain removal by furin-like convertases in the TGN\\u2014and the minimal/essential domain architecture for procollagen cleavage and secretion.\",\n      \"evidence\": \"Furin inhibition, recombinant furin cleavage, RSRR-site mutagenesis, domain deletion/swap, secretion and cleavage assays, immunofluorescence\",\n      \"pmids\": [\"12637537\", \"12637569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of the proenzyme or CUB-substrate interface\", \"Functional role of individual PTMs untested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified latent myostatin as a BMP1 substrate, establishing a role in regulating muscle mass.\",\n      \"evidence\": \"In vitro cleavage of myostatin propeptide, cleavage-resistant mutant, in vivo injection into adult mice\",\n      \"pmids\": [\"14671324\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological setting and tissue context of endogenous myostatin activation by BMP1 not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed BMP1 releases the angiostatic LG3 fragment from perlecan/endorepellin, connecting the protease to angiogenesis control.\",\n      \"evidence\": \"In vitro and cell-based endorepellin cleavage, mutagenesis, angiogenic assays, modeling\",\n      \"pmids\": [\"15591058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo requirement for BMP1 in LG3 generation and angiogenesis not established\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Mapped the determinants of BMP1 substrate selectivity\\u2014CUB domains and PCPE-1 specificity\\u2014distinguishing fibrillar procollagen processing from Chordin cleavage.\",\n      \"evidence\": \"Domain swaps between BMP1 and mTLL-2, PCPE-1 enhancement across multiple substrates, procollagen conformational variants\",\n      \"pmids\": [\"15834133\", \"15817489\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CUB1-conferred Chordin specificity not solved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected BMP1 to TGF-\\u03b2 mobilization via LTBP1 cleavage and revealed a TGF-\\u03b2-inducible feed-forward loop in tissue remodeling.\",\n      \"evidence\": \"In vitro LTBP1 cleavage, MEF cultures, MMP2 inhibitor/genetic experiments, in vivo evidence\",\n      \"pmids\": [\"17015622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"BMP1 liberates the latent complex but does not directly activate TGF-\\u03b2; downstream activation depends on other proteases\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated that non-catalytic domains, not the protease domain alone, enforce physiological substrate specificity, and broadened substrates into lipoprotein metabolism via pro-apoA1.\",\n      \"evidence\": \"Full-length vs. isolated protease domain on multiple substrates; recombinant/antibody/siRNA assays for pro-apoA1 in HepG2 and CHO cells\",\n      \"pmids\": [\"17516847\", \"17580958\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"pro-apoA1 work from single lab, in vivo HDL relevance untested\", \"No residue-level mapping of CUB selectivity contacts\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established positive cofactor and substrate links in collagen cross-linking: periostin enhances BMP1-mediated LOX activation, and BMP1 processes DSPP.\",\n      \"evidence\": \"Co-IP and solid-phase binding, periostin-null osteoblasts; in vitro DSPP cleavage with motif mutagenesis across three isoforms\",\n      \"pmids\": [\"20181949\", \"20079836\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of periostin-mediated ECM deposition of BMP1 only partially defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established BMP1 mutation as a cause of human autosomal recessive osteogenesis imperfecta through loss of procollagen C-propeptide processing.\",\n      \"evidence\": \"Patient fibroblast processing assays, WT vs. mutant mTLD overexpression, homozygosity mapping\",\n      \"pmids\": [\"22052668\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype range across BMP1 mutations not fully defined at this stage\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked BMP1 to bone matrix maturation and high-bone-mass OI phenotypes, with conserved osteogenic function in zebrafish.\",\n      \"evidence\": \"Whole-exome sequencing, secretion assays, zebrafish bmp1a mutants, bone histology/biochemistry\",\n      \"pmids\": [\"22482805\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking impaired secretion to increased bone mineral density not fully resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the in vivo skeletal consequences of combined BMP1/TLL1 loss and broadened TGF-\\u03b2 pathway regulation through betaglycan and CD109 cleavage.\",\n      \"evidence\": \"Conditional Bmp1/Tll1 double KO skeletal phenotyping; iTRAQ proteomics, in vitro cleavage with MS site mapping, SMAD2 assays in primary keratocytes\",\n      \"pmids\": [\"24419319\", \"25260970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking BMP1 loss to canonical Wnt induction in bone not established\", \"Net signaling outcome of co-receptor cleavage may be context-dependent\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Confirmed in humans that BMP1 deficiency impairs both procollagen and prodecorin processing, disrupting heterotypic collagen fibril assembly.\",\n      \"evidence\": \"Patient fibroblast processing assays, immunofluorescence for collagens I/V, dermal TEM\",\n      \"pmids\": [\"25656619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of decorin defect vs. collagen defect to the phenotype unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined tissue-level skin phenotypes of BMP1-like proteinase loss and enumerated cofactor PTMs and a positive enhancer (WFIKKN1) for myostatin processing.\",\n      \"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\",\n      \"pmids\": [\"27363389\", \"26944735\", \"27782377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of identified PTMs untested by mutagenesis\", \"Collagen VII processing attributed to non-BMP1 proteases\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Refined lysyl oxidase activation and added collagen VI/endotrophin to the substrate set, showing coordinated processing with ADAMTS and furin proteases.\",\n      \"evidence\": \"Cellular models, immunoprecipitation, LOX activity and binding assays, isotopic MS site mapping, EM/immunofluorescence\",\n      \"pmids\": [\"31152061\", \"31346034\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological balance between BMP1 and ADAMTS cleavage of LOX/LOXL1 in vivo unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established BMP1 as the major nonredundant procollagen C-proteinase in lung fibroblasts and extended its TGF-\\u03b2-modulating role via thrombospondin-1 cleavage.\",\n      \"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\",\n      \"pmids\": [\"33206546\", \"32636307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue specificity of BMP1 nonredundancy vs. mTLL-1 not generalized beyond lung fibroblasts\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Tested and refuted a requirement for BMP1 in bleomycin-induced lung fibrosis and resolved differential LOXL1 cleavage between BMP1 and ADAMTS14.\",\n      \"evidence\": \"Inducible Bmp1 cKO in bleomycin model with CICP measurement; cellular genetic models and proteomics for LOXL1\",\n      \"pmids\": [\"35361882\", \"35328709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative fibrosis result from single lab/model; redundancy with mTLL-1 may mask requirement\", \"Functional consequences of distinct LOXL1 cleavage products not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"37235726\", \"38049428\", \"37338142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo cholesterol/HDL phenotypes of BMP1-mediated LDLR cleavage untested\", \"O-fucosylation findings from single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How BMP1's CUB domains and cofactors structurally select among its many substrates, and what determines tissue-specific nonredundancy versus mTLL-1, remain unresolved.\",\n      \"evidence\": \"No high-resolution structure of full-length BMP1 or substrate/cofactor complexes in the corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of CUB-substrate recognition\", \"In vivo hierarchy of physiological substrates not ranked\", \"Tissue determinants of BMP1 vs. mTLL-1 redundancy unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 3, 7, 10, 19, 23, 24, 25, 29]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 5, 10, 21]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 10, 14, 25]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 8, 20, 21, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 19, 25, 31]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 6, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 17, 18, 20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TLL1\", \"PCPE-1\", \"PCPE-2\", \"periostin\", \"CHRD\", \"WFIKKN1\", \"sizzled\", \"CD109\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}