{"gene":"MASP2","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2012,"finding":"In normal human serum, MASP-2 activation strictly depends on MASP-1; MASP-1 acts as the exclusive activator of MASP-2, and inhibition of MASP-1 prevents autoactivation of MASP-2. Furthermore, MASP-1 produces 60% of C2a responsible for C3 convertase formation.","method":"Monospecific inhibitors against MASP-1 and MASP-2 used in functional complement activation assays in human serum","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — unique monospecific inhibitors with functional readouts, replicated mechanistic conclusion","pmids":["22691502"],"is_preprint":false},{"year":1999,"finding":"MASP-2 is encoded by the MASP-2 gene and a truncated form (sMAP/MAp19) is produced by alternative polyadenylation using a sMAP-specific exon with an in-frame stop codon; MAp19 consists of the first two domains of MASP-2 (CUB1 and EGF-like) plus four additional C-terminal amino acids and is a component of the MBL-MASP complex.","method":"cDNA cloning, sequence analysis, and biochemical characterization of MBL-MASP complex components","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 1 — molecular cloning with sequence validation; independently replicated across multiple labs","pmids":["10330290"],"is_preprint":false},{"year":2004,"finding":"MASP-2 cleaves complement components C4 and C2 to form the C3 convertase C4b2a; its substrate specificity differs from MASP-1, with MASP-2 showing very low activity against fluorescent amide substrates but efficiently cleaving C4 as a natural protein substrate. C1-inhibitor inhibits both MASP-1 and MASP-2.","method":"In vitro cleavage assays using recombinant and serum-derived MASPs with fluorescent amide substrates and natural protein substrates; inhibitor profiling","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic assays with recombinant proteins and defined substrates/inhibitors","pmids":["14725788"],"is_preprint":false},{"year":2007,"finding":"MASP-2 substrate specificity requires P1 position and S2/S3 subsites (Gly at P2, hydrophobic at P3); MASP-2 is up to 1000 times more catalytically active than C1s toward C2, C4, and C1-inhibitor cleavage sequences; C1-inhibitor inhibits MASP-2 50-fold faster than C1s, identifying MASP-2 as a major physiological target of C1-inhibitor.","method":"Randomized substrate phage display library, peptide substrate cleavage assays, serpin inhibition kinetics","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with defined substrates and mutagenesis-level substrate profiling","pmids":["17709141"],"is_preprint":false},{"year":2004,"finding":"X-ray crystal structure of MAp19 (the alternative splice product of MASP-2) resolved to 2.5 Å reveals a head-to-tail homodimer stabilized by Ca2+ ions; point mutations at Tyr59, Asp60, Glu83, Asp105, Tyr106, and Glu109 in the CUB1 module abolish or strongly decrease interaction with MBL and L-ficolin, defining the common binding site.","method":"X-ray crystallography (2.5 Å resolution) and surface plasmon resonance with point mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with mutagenesis and SPR binding validation","pmids":["15117939"],"is_preprint":false},{"year":2000,"finding":"MASP-1, MASP-2, and MAp19 are found exclusively associated with MBL in serum (not with C1q); C1r and C1s associate exclusively with C1q (not MBL); the MASPs and MAp19 require both high salt and calcium chelation (EDTA) to fully dissociate from MBL; the bulk of MASP-1 and MAp19 circulates as large complexes not bound to MBL.","method":"Serum fractionation, gel-permeation chromatography, complement activation assays in C1r-deficient serum","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal association studies with multiple biochemical fractionation approaches","pmids":["10878362"],"is_preprint":false},{"year":2011,"finding":"MAp19 does not compete with MASP-2 for binding to MBL at physiological concentrations, nor does it inhibit MASP-2-mediated complement activation; both MASP-2 and MAp19 are predominantly expressed in hepatocytes; high levels of MAp19 are found in urine where MASP-2 is absent.","method":"Quantitative ELISA with monoclonal antibodies, complement activation assays, immunohistochemistry, qRT-PCR","journal":"Journal of immunological methods","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods with quantitative assays correcting prior claims","pmids":["21871896"],"is_preprint":false},{"year":2006,"finding":"MASP-1 cooperates with MASP-2 in generating the C3 convertase through the MBL pathway; depletion of MASP-1, MASP-2, and MASP-3 abolishes C3b deposition on mannan, and reconstitution with both MASP-1 and MASP-2 shows synergistic effect; MASP-3 inhibits this process; the cooperation requires C4 and C2 but not factor B.","method":"Complement depletion and reconstitution assays measuring C3b deposition on mannan-coated surfaces","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 2 — epistasis-type reconstitution experiment with defined complement component depletions","pmids":["17182967"],"is_preprint":false},{"year":2013,"finding":"MASP-1 and MASP-2 form heterodimeric co-complexes when bridged by MBL or ficolins; these co-complexes have a functional role in complement activation; MAp44 may inhibit complement by disrupting MASP-1–MASP-2 co-complexes and thereby impairing MASP-1-mediated transactivation of MASP-2.","method":"Native PAGE, size exclusion chromatography, complement activation assays, and inhibition studies with MAp44","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple biochemical methods demonstrating complex formation and functional consequences","pmids":["23785123"],"is_preprint":false},{"year":2011,"finding":"MASP-2 requires multiple domains for high-affinity interaction with its substrate C4: the CCP1-CCP2-SP combination binds C4 with much higher affinity than CCP1-CCP2 or SP domain alone, indicating cooperative interaction; mutation of K342A in CCP1 abolishes binding to C4 and C4b.","method":"Binding assays with active and catalytically inactive recombinant MASP-2 domain constructs; site-directed mutagenesis","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 1 — in vitro binding assays with domain deletion constructs and mutagenesis","pmids":["22071314"],"is_preprint":false},{"year":1999,"finding":"Rat and mouse MASP-2 are components of the MBL lectin pathway activation complex; both MASP-2 and MAp19 are encoded by a single structural MASP-2 gene (as in humans) and are exclusively synthesized in the liver; rat MASP-2 cleaves complement component C4.","method":"cDNA cloning, Southern blot, PCR, hepatic biosynthesis demonstrated by tissue expression analysis, C4 cleavage assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — molecular cloning with functional C4 cleavage validation and tissue-specific expression","pmids":["10586086"],"is_preprint":false},{"year":2006,"finding":"Carp MASP2 associates with MBL homologs and cleaves native human C4 into C4b (but not C4i with hydrolyzed thioester), demonstrating that MASP2 and its C4-cleaving function arose before the emergence of bony fish.","method":"Protein isolation, molecular cloning, phylogenetic analysis, C4 cleavage activity assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro functional assay in an ortholog, single study","pmids":["17015733"],"is_preprint":false},{"year":2016,"finding":"MASP-2 critically mediates cerebral ischemia-reperfusion injury independently of MASP-1: MASP-2-deficient mice show significantly reduced neurological deficits, infarct volumes, C3 deposition, and pro-inflammatory microglia phenotype after transient ischemia, while MASP-1/3-deficient mice are not protected.","method":"Genetic knockout mice (MASP-2−/−, MASP-1/3−/−, fB−/−) and inhibitory antibody in tMCAO/3VO stroke models; immunohistochemistry, behavioral, and histopathological assessment","journal":"Journal of neuroinflammation","confidence":"High","confidence_rationale":"Tier 2 — clean KO with specific phenotypic readout, multiple orthogonal methods and genetic controls","pmids":["27577570"],"is_preprint":false},{"year":2014,"finding":"Tissue factor pathway inhibitor (TFPI) selectively inhibits MASP-2 activity without affecting MASP-1 or classical pathway proteases C1s/C1r; the Kunitz-2 domain of TFPI is required for this inhibition, as demonstrated by domain-specific antibody blocking.","method":"Ex vivo lectin pathway C4-deposition assay, fluid-phase chromogenic MASP-2 activity assay, domain-specific monoclonal antibody blocking","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 — functional assays with domain-specific antibodies establishing mechanism of inhibition","pmids":["25359215"],"is_preprint":false},{"year":2014,"finding":"MASP-1 and MASP-2 CUB1-EGF-CUB2 fragments form Ca2+-dependent homodimers that can exchange subunits to form MASP-1:MASP-2 heterodimers after dissociation/re-association, providing structural basis for the co-complex formation required for transactivation.","method":"Size exclusion chromatography, native PAGE, EDTA dissociation and re-calcification reassociation experiments with recombinant domain fragments","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical reconstitution of heterodimer formation, single study","pmids":["24424083"],"is_preprint":false},{"year":2019,"finding":"MASP-2 variants G634R and R203W in human patients cause functional defects including reduced (R203W) or abolished (G634R) protein secretion, loss of capability to cleave MASP-2 precursor into its active form (G634R), and reduced antiviral activity in vivo; MBL-deficient mice have decreased survival and increased HSV-1 brain burden, linking MASP-2 function to protection against herpes simplex encephalitis.","method":"In vitro expression of variant proteins assessing secretion and autoactivation cleavage; murine HSE model with MBL-deficient mice","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro functional characterization of variants plus in vivo mouse model, single lab","pmids":["31869396"],"is_preprint":false},{"year":2005,"finding":"Mouse ficolin A and its splicing variant, but not ficolin B, bind MASP-2 and form complexes with potent complement-activating capacity; sMAP (MAp19) competes with MASP-2 for association with ficolin A and inhibits complement activation by the ficolin A/MASP-2 complex, indicating a regulatory role for MAp19.","method":"Recombinant protein expression, binding assays, and complement activation assays","journal":"Immunogenetics","confidence":"Medium","confidence_rationale":"Tier 2 — binding and functional assays with recombinant proteins, single lab","pmids":["16328467"],"is_preprint":false},{"year":2002,"finding":"MASP-2 shares identical domain structure with MASP-1, MASP-3, C1r, and C1s (comprising CUB1-EGF-CUB2-CCP1-CCP2-serine protease domains); MASP-2 is the protease responsible for activating C4 and C2 to generate the C3 convertase C4bC2b; MASP-1 and MASP-3 are alternative splice products of the MASP1/3 gene, while MASP-2 and MAp19 are alternative products of the MASP-2 gene.","method":"Molecular cloning, sequence analysis, and functional complement assays","journal":"Immunobiology","confidence":"High","confidence_rationale":"Tier 2 — replicated across multiple labs, established domain organization and functional role","pmids":["12396007"],"is_preprint":false},{"year":2020,"finding":"MASP-2 (the effector enzyme of the lectin pathway) is elevated in thrombotic microangiopathies; plasmas from TMA patients induce microvascular endothelial cell caspase 8 activation, which is suppressed by the anti-MASP-2 antibody narsoplimab, demonstrating that MASP-2-mediated lectin pathway activation directly contributes to endothelial injury in TMAs.","method":"ELISA for MASP-2 levels, in vitro MVEC caspase 8 activity assay with patient plasmas and narsoplimab inhibition","journal":"Clinical and experimental immunology","confidence":"Medium","confidence_rationale":"Tier 2 — functional in vitro assay with specific antibody inhibition and patient samples, single lab","pmids":["32681658"],"is_preprint":false},{"year":2022,"finding":"MASP-2 and MASP-3 inhibitory monoclonal antibodies markedly reduce complement activation (Bb, C4d, C5a, complement deposition in liver/kidney/lung), hepatic inflammation markers (NF-κB, VCAM-1, ICAM-1, E-selectin), and microvascular stasis (vaso-occlusion) in sickle cell disease mice after hypoxia-reoxygenation or hemoglobin challenge.","method":"In vivo mouse model (Townes SS mice) with MASP-2 and MASP-3 inhibitory mAbs, intravital microscopy for microvascular stasis, ELISA and immunohistochemistry for complement markers","journal":"Translational research","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO-equivalent antibody inhibition with specific phenotypic readouts, single lab","pmids":["35878790"],"is_preprint":false}],"current_model":"MASP-2 is a serine protease of the lectin complement pathway that, upon activation exclusively by MASP-1 (which transactivates it within MBL/ficolin co-complexes), cleaves C4 and C2 to generate the C3 convertase C4bC2a; its catalytic activity is mediated by cooperative interactions of its CCP1-CCP2-SP domains with C4, is regulated primarily by C1-inhibitor (and also TFPI via its Kunitz-2 domain), and its alternative splice product MAp19 (sharing CUB1-EGF domains) circulates at comparable concentrations but does not significantly inhibit MASP-2 activity in vivo; MASP-2-dependent complement activation drives ischemia-reperfusion injury, thrombotic microangiopathies, and vaso-occlusion in sickle cell disease."},"narrative":{"teleology":[{"year":1999,"claim":"Molecular cloning established that a single MASP-2 gene encodes both the full-length serine protease and a truncated splice variant (MAp19/sMAP) sharing CUB1-EGF domains, resolving the genetic origin and domain organization of the lectin pathway protease.","evidence":"cDNA cloning and sequence analysis in human, rat, and mouse with tissue expression profiling confirming liver-restricted synthesis","pmids":["10330290","10586086"],"confidence":"High","gaps":["Regulatory mechanisms controlling alternative splicing of MASP-2 vs. MAp19 not defined","Post-translational processing steps not characterized"]},{"year":2002,"claim":"The complete domain architecture of MASP-2 (CUB1-EGF-CUB2-CCP1-CCP2-SP) was mapped and its exclusive role in cleaving C4 and C2 to form the C3 convertase was confirmed, distinguishing it functionally from MASP-1 and MASP-3.","evidence":"Molecular cloning, sequence comparison with C1r/C1s family members, and functional complement assays","pmids":["12396007"],"confidence":"High","gaps":["Structural basis for differential substrate recognition vs. C1s not resolved"]},{"year":2004,"claim":"Enzymatic characterization defined MASP-2's substrate specificity—high activity toward native C4 but low activity on small fluorescent substrates—and identified C1-inhibitor as its physiological regulator, while crystal structure of MAp19 at 2.5 Å revealed the CUB1-domain residues critical for MBL/ficolin binding.","evidence":"In vitro cleavage assays with recombinant MASPs, serpin inhibition kinetics, X-ray crystallography of MAp19 with site-directed mutagenesis and SPR","pmids":["14725788","15117939"],"confidence":"High","gaps":["Full-length MASP-2 structure in complex with C4 not determined","Whether MAp19 has an independent biological function beyond MBL binding remained open"]},{"year":2006,"claim":"Reconstitution experiments demonstrated that MASP-1 and MASP-2 cooperate synergistically in C3 convertase generation through the lectin pathway, with MASP-3 acting as an inhibitor, establishing the functional hierarchy among MASPs.","evidence":"Complement depletion and reconstitution assays measuring C3b deposition on mannan-coated surfaces","pmids":["17182967"],"confidence":"High","gaps":["Whether MASP-1's role was direct activation of MASP-2 or parallel C2 cleavage was not yet distinguished"]},{"year":2007,"claim":"Substrate phage display and kinetic analysis revealed that MASP-2 is up to 1000-fold more catalytically active than C1s toward C2 and C4 cleavage sequences, and that C1-inhibitor inhibits MASP-2 50-fold faster than C1s, redefining MASP-2 as the major physiological target of this serpin in complement regulation.","evidence":"Randomized substrate phage display, peptide cleavage assays, serpin inhibition kinetics","pmids":["17709141"],"confidence":"High","gaps":["In vivo contribution of C1-inhibitor to MASP-2 regulation vs. other serpins not quantified"]},{"year":2011,"claim":"Domain-mapping experiments established that MASP-2's CCP1-CCP2-SP domains cooperate for high-affinity C4 binding and that K342 in CCP1 is essential, while quantitative serum measurements showed MAp19 does not inhibit MASP-2 complement activity at physiological concentrations, correcting prior claims.","evidence":"Binding assays with domain deletion constructs and site-directed mutagenesis; quantitative ELISA, complement activation assays, immunohistochemistry","pmids":["22071314","21871896"],"confidence":"High","gaps":["Full structural model of MASP-2–C4 interface not available","Biological function of circulating and urinary MAp19 unknown"]},{"year":2012,"claim":"Using monospecific inhibitors in human serum, MASP-1 was identified as the exclusive physiological activator of MASP-2, resolving the long-standing question of whether MASP-2 can autoactivate in vivo.","evidence":"Monospecific MASP-1 and MASP-2 inhibitors in functional lectin pathway activation assays in normal human serum","pmids":["22691502"],"confidence":"High","gaps":["Whether MASP-2 can autoactivate under any non-physiological or pathological condition remains untested"]},{"year":2013,"claim":"The structural basis for MASP-1–MASP-2 transactivation was elucidated: MBL/ficolins bridge Ca²⁺-dependent CUB1-EGF-CUB2 heterodimers that enable MASP-1 to directly cleave MASP-2, and MAp44 disrupts these co-complexes as an endogenous inhibitor.","evidence":"Native PAGE, SEC, Ca²⁺-dependent subunit exchange experiments, and complement activation assays with MAp44 inhibition","pmids":["23785123","24424083"],"confidence":"High","gaps":["Stoichiometry and architecture of native MBL-MASP co-complexes on target surfaces not resolved","Quantitative contribution of MAp44 regulation in vivo not measured"]},{"year":2014,"claim":"TFPI was identified as a selective physiological inhibitor of MASP-2 that does not affect MASP-1 or classical pathway proteases, with the Kunitz-2 domain mediating this specificity—establishing a cross-talk mechanism between coagulation and lectin pathway regulation.","evidence":"Ex vivo C4-deposition assay, chromogenic MASP-2 activity assay, domain-specific monoclonal antibody blocking of TFPI","pmids":["25359215"],"confidence":"High","gaps":["In vivo relevance of TFPI–MASP-2 inhibition not validated in animal models","Whether TFPI regulation of MASP-2 affects coagulation parameters not tested"]},{"year":2016,"claim":"MASP-2 was demonstrated to be the critical driver of cerebral ischemia-reperfusion injury, as MASP-2-knockout mice showed reduced infarct volumes and neuroinflammation while MASP-1/3-knockout mice were unprotected, establishing a MASP-1-independent pathogenic role for MASP-2 in stroke.","evidence":"Genetic knockout mice (MASP-2⁻/⁻, MASP-1/3⁻/⁻) in tMCAO and 3VO stroke models with histopathological, immunohistochemical, and behavioral readouts","pmids":["27577570"],"confidence":"High","gaps":["MASP-1-independent activation mechanism of MASP-2 in this setting not explained","Whether MASP-2 acts via C3 convertase or alternative substrates in neuroinflammation not distinguished"]},{"year":2020,"claim":"Lectin pathway-dependent endothelial injury in thrombotic microangiopathies and sickle cell vaso-occlusion was shown to depend on MASP-2, as anti-MASP-2 antibodies suppressed caspase-8 activation in endothelial cells exposed to TMA plasmas and reduced complement deposition, inflammation, and microvascular stasis in sickle cell mice.","evidence":"In vitro MVEC caspase-8 assay with narsoplimab and patient plasmas; in vivo Townes SS mouse model with MASP-2 inhibitory mAbs, intravital microscopy, ELISA","pmids":["32681658","35878790"],"confidence":"Medium","gaps":["Downstream signaling pathway from MASP-2 to endothelial caspase-8 not defined","Clinical efficacy of MASP-2 inhibition in human TMA/SCD not established by these studies","Single-lab findings for each disease model"]},{"year":null,"claim":"Key unresolved questions include the full structural basis of the MASP-2–C4 complex, the MASP-1-independent activation mechanism observed in ischemia-reperfusion, the biological function of MAp19, and whether MASP-2 cleaves non-complement substrates that contribute to its pathogenic roles.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure of MASP-2 in complex with C4","MAp19 function remains unknown","Non-complement substrates of MASP-2 not systematically profiled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,3,7,9,17]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[2,3,11]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[5,6,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,7,8,12,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,18,19]}],"complexes":["MBL-MASP complex","Ficolin-MASP complex"],"partners":["MASP1","MBL2","FCN1","FCN2","SERPING1","TFPI","C4","C2"],"other_free_text":[]},"mechanistic_narrative":"MASP-2 is the key effector serine protease of the lectin complement pathway, cleaving C4 and C2 to assemble the C3 convertase C4bC2a on pathogen surfaces and damaged host tissues. MASP-2 is exclusively activated by MASP-1 through transactivation within MBL- or ficolin-bridged heterodimeric co-complexes that form via Ca²⁺-dependent CUB1-EGF-CUB2 dimerization, and its catalytic engagement of C4 requires cooperative binding across the CCP1-CCP2-SP domains [PMID:22691502, PMID:23785123, PMID:22071314]. Its activity is regulated by C1-inhibitor, which inhibits MASP-2 50-fold faster than C1s, and by TFPI via its Kunitz-2 domain; an alternative splice product, MAp19, shares the CUB1-EGF domains but does not significantly inhibit MASP-2-dependent complement activation at physiological concentrations [PMID:17709141, PMID:25359215, PMID:21871896]. MASP-2-dependent lectin pathway activation drives ischemia-reperfusion injury in the brain and contributes to endothelial damage in thrombotic microangiopathies and vaso-occlusion in sickle cell disease [PMID:27577570, PMID:32681658, PMID:35878790]."},"prefetch_data":{"uniprot":{"accession":"O00187","full_name":"Mannan-binding lectin serine protease 2","aliases":["MBL-associated serine protease 2","Mannose-binding protein-associated serine protease 2","MASP-2"],"length_aa":686,"mass_kda":75.7,"function":"Precursor of a serum protease that activates the lectin pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system (PubMed:11527969, PubMed:22691502). The lectin complement system is activated following association of lectins, such as MBL2, FCN1, FCN2 or FCN3, to carbohydrates on the pathogen surface (PubMed:22691502, PubMed:22966085). MASP2 is cleaved and activated by MASP1 in response to lectin-binding to pathogen carbohydrates (PubMed:10946292, PubMed:22949645, PubMed:22966085, PubMed:9087411). Can activate prothrombin to thrombin (PubMed:39924859) Serine protease component of the lectin complement pathway, which catalyzes cleavage and activation of C2 and C4, the next components of the complement pathway","subcellular_location":"Secreted; Cell surface","url":"https://www.uniprot.org/uniprotkb/O00187/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MASP2","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MASP2","total_profiled":1310},"omim":[{"mim_id":"614372","title":"MANNOSE-BINDING LECTIN DEFICIENCY; MBLD","url":"https://www.omim.org/entry/614372"},{"mim_id":"613860","title":"FICOLIN 3 DEFICIENCY","url":"https://www.omim.org/entry/613860"},{"mim_id":"613791","title":"MASP2 DEFICIENCY","url":"https://www.omim.org/entry/613791"},{"mim_id":"606860","title":"COMPLEMENT COMPONENT 1 INHIBITOR; C1NH","url":"https://www.omim.org/entry/606860"},{"mim_id":"605102","title":"MANNAN-BINDING LECTIN SERINE PROTEASE 2; MASP2","url":"https://www.omim.org/entry/605102"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Golgi apparatus","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":452.9}],"url":"https://www.proteinatlas.org/search/MASP2"},"hgnc":{"alias_symbol":["Map19","sMAP","MAP-2"],"prev_symbol":["MASP1P1"]},"alphafold":{"accession":"O00187","domains":[{"cath_id":"2.60.120.290","chopping":"28-139","consensus_level":"high","plddt":93.363,"start":28,"end":139},{"cath_id":"2.60.120.290","chopping":"185-298","consensus_level":"medium","plddt":94.4473,"start":185,"end":298},{"cath_id":"2.10.70.10","chopping":"300-364","consensus_level":"medium","plddt":93.4923,"start":300,"end":364},{"cath_id":"2.10.70.10","chopping":"376-433","consensus_level":"high","plddt":91.4043,"start":376,"end":433},{"cath_id":"2.40.10.10","chopping":"450-684","consensus_level":"medium","plddt":90.1106,"start":450,"end":684}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00187","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00187-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00187-F1-predicted_aligned_error_v6.png","plddt_mean":89.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MASP2","jax_strain_url":"https://www.jax.org/strain/search?query=MASP2"},"sequence":{"accession":"O00187","fasta_url":"https://rest.uniprot.org/uniprotkb/O00187.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00187/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00187"}},"corpus_meta":[{"pmid":"2842685","id":"PMC_2842685","title":"Insulin-stimulated MAP-2 kinase phosphorylates and activates ribosomal protein S6 kinase II.","date":"1988","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/2842685","citation_count":1005,"is_preprint":false},{"pmid":"1484385","id":"PMC_1484385","title":"The role of microtubule-associated protein 2 (MAP-2) in neuronal growth, plasticity, and degeneration.","date":"1992","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/1484385","citation_count":310,"is_preprint":false},{"pmid":"6251448","id":"PMC_6251448","title":"Structure and phosphorylation of microtubule-associated protein 2 (MAP 2).","date":"1980","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/6251448","citation_count":257,"is_preprint":false},{"pmid":"6270156","id":"PMC_6270156","title":"A protein kinase bound to the projection portion of MAP 2 (microtubule-associated protein 2).","date":"1981","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/6270156","citation_count":232,"is_preprint":false},{"pmid":"6343400","id":"PMC_6343400","title":"Association of microtubule-associated protein 2 (MAP 2) with microtubules and intermediate filaments in cultured brain cells.","date":"1983","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/6343400","citation_count":188,"is_preprint":false},{"pmid":"7965042","id":"PMC_7965042","title":"DLX-2, MASH-1, and MAP-2 expression and bromodeoxyuridine incorporation define molecularly distinct cell populations in the embryonic mouse forebrain.","date":"1994","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/7965042","citation_count":185,"is_preprint":false},{"pmid":"22691502","id":"PMC_22691502","title":"Revised mechanism of complement lectin-pathway activation revealing the role of serine protease MASP-1 as the exclusive activator of MASP-2.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22691502","citation_count":163,"is_preprint":false},{"pmid":"1667578","id":"PMC_1667578","title":"ERKs, extracellular signal-regulated MAP-2 kinases.","date":"1991","source":"Current opinion in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/1667578","citation_count":142,"is_preprint":false},{"pmid":"10330290","id":"PMC_10330290","title":"A truncated form of mannose-binding lectin-associated serine protease (MASP)-2 expressed by alternative polyadenylation is a component of the lectin complement pathway.","date":"1999","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10330290","citation_count":140,"is_preprint":false},{"pmid":"33163724","id":"PMC_33163724","title":"Safety, Tolerability and Efficacy of Narsoplimab, a Novel MASP-2 Inhibitor for the Treatment of IgA Nephropathy.","date":"2020","source":"Kidney international reports","url":"https://pubmed.ncbi.nlm.nih.gov/33163724","citation_count":127,"is_preprint":false},{"pmid":"2115775","id":"PMC_2115775","title":"The tubulin-binding sequence of brain microtubule-associated proteins, tau and MAP-2, is also involved in actin binding.","date":"1990","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/2115775","citation_count":125,"is_preprint":false},{"pmid":"14725788","id":"PMC_14725788","title":"Differential substrate and inhibitor profiles for human MASP-1 and MASP-2.","date":"2004","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14725788","citation_count":113,"is_preprint":false},{"pmid":"15964096","id":"PMC_15964096","title":"Altered expression of MAP-2, GAP-43, and synaptophysin in the hippocampus of rats with chronic cerebral hypoperfusion correlates with cognitive impairment.","date":"2005","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/15964096","citation_count":111,"is_preprint":false},{"pmid":"33973408","id":"PMC_33973408","title":"hu.MAP 2.0: integration of over 15,000 proteomic experiments builds a global compendium of human multiprotein assemblies.","date":"2021","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/33973408","citation_count":98,"is_preprint":false},{"pmid":"12396007","id":"PMC_12396007","title":"The mannan-binding lectin-associated serine proteases (MASPs) and MAp19: four components of the lectin pathway activation complex encoded by two genes.","date":"2002","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/12396007","citation_count":96,"is_preprint":false},{"pmid":"9605349","id":"PMC_9605349","title":"Disruption of MAP-2 immunostaining in rat hippocampus after traumatic brain injury.","date":"1998","source":"Journal of neurotrauma","url":"https://pubmed.ncbi.nlm.nih.gov/9605349","citation_count":91,"is_preprint":false},{"pmid":"10878362","id":"PMC_10878362","title":"Interaction of C1q and mannan-binding lectin (MBL) with C1r, C1s, MBL-associated serine proteases 1 and 2, and the MBL-associated protein MAp19.","date":"2000","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/10878362","citation_count":89,"is_preprint":false},{"pmid":"3113673","id":"PMC_3113673","title":"An immunocytochemical analysis of the ontogeny of the microtubule-associated proteins MAP-2 and Tau in the nervous system of the rat.","date":"1987","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/3113673","citation_count":82,"is_preprint":false},{"pmid":"9588626","id":"PMC_9588626","title":"Making sense of the multiple MAP-2 transcripts and their role in the neuron.","date":"1998","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/9588626","citation_count":74,"is_preprint":false},{"pmid":"17182967","id":"PMC_17182967","title":"Cooperation between MASP-1 and MASP-2 in the generation of C3 convertase through the MBL pathway.","date":"2006","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17182967","citation_count":73,"is_preprint":false},{"pmid":"7566447","id":"PMC_7566447","title":"Abnormal expression of microtubule-associated protein 2 (MAP-2) in neocortex in Rett syndrome.","date":"1995","source":"Neuropediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/7566447","citation_count":66,"is_preprint":false},{"pmid":"8473887","id":"PMC_8473887","title":"Ammonium injection induces an N-methyl-D-aspartate receptor-mediated proteolysis of the microtubule-associated protein MAP-2.","date":"1993","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8473887","citation_count":65,"is_preprint":false},{"pmid":"17709141","id":"PMC_17709141","title":"Elucidation of the substrate specificity of the MASP-2 protease of the lectin complement pathway and identification of the enzyme as a major physiological target of the serpin, C1-inhibitor.","date":"2007","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17709141","citation_count":65,"is_preprint":false},{"pmid":"9506951","id":"PMC_9506951","title":"Complex formation of SMAP/KAP3, a KIF3A/B ATPase motor-associated protein, with a human chromosome-associated polypeptide.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9506951","citation_count":63,"is_preprint":false},{"pmid":"8900189","id":"PMC_8900189","title":"SMAP, an Smg GDS-associating protein having arm repeats and phosphorylated by Src tyrosine kinase.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8900189","citation_count":60,"is_preprint":false},{"pmid":"21871896","id":"PMC_21871896","title":"MAp19, the alternative splice product of the MASP2 gene.","date":"2011","source":"Journal of immunological methods","url":"https://pubmed.ncbi.nlm.nih.gov/21871896","citation_count":59,"is_preprint":false},{"pmid":"8020109","id":"PMC_8020109","title":"Antisense MAP-2 oligonucleotides induce changes in microtubule assembly and neuritic elongation in pre-existing neurites of rat cortical neurons.","date":"1994","source":"Cell motility and the cytoskeleton","url":"https://pubmed.ncbi.nlm.nih.gov/8020109","citation_count":57,"is_preprint":false},{"pmid":"3091608","id":"PMC_3091608","title":"Identification of a MAP 2-like ATP-binding protein associated with axoplasmic vesicles that translocate on isolated microtubules.","date":"1986","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/3091608","citation_count":57,"is_preprint":false},{"pmid":"9341200","id":"PMC_9341200","title":"Calcium-stimulated phosphorylation of MAP-2 in pancreatic betaTC3-cells is mediated by Ca2+/calmodulin-dependent kinase II.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9341200","citation_count":55,"is_preprint":false},{"pmid":"2745548","id":"PMC_2745548","title":"Cell cycle-dependent changes in the dynamics of MAP 2 and MAP 4 in cultured cells.","date":"1989","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/2745548","citation_count":51,"is_preprint":false},{"pmid":"23785123","id":"PMC_23785123","title":"Co-complexes of MASP-1 and MASP-2 associated with the soluble pattern-recognition molecules drive lectin pathway activation in a manner inhibitable by MAp44.","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/23785123","citation_count":50,"is_preprint":false},{"pmid":"17015733","id":"PMC_17015733","title":"Lectin pathway of bony fish complement: identification of two homologs of the mannose-binding lectin associated with MASP2 in the common carp (Cyprinus carpio).","date":"2006","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17015733","citation_count":50,"is_preprint":false},{"pmid":"22221294","id":"PMC_22221294","title":"MBL2, MASP2, AMELX, and ENAM gene polymorphisms and dental caries in Polish children.","date":"2012","source":"Oral diseases","url":"https://pubmed.ncbi.nlm.nih.gov/22221294","citation_count":49,"is_preprint":false},{"pmid":"15117939","id":"PMC_15117939","title":"The X-ray structure of human mannan-binding lectin-associated protein 19 (MAp19) and its interaction site with mannan-binding lectin and L-ficolin.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15117939","citation_count":49,"is_preprint":false},{"pmid":"2153774","id":"PMC_2153774","title":"Ganglioside-enhanced neurite growth: evidence for a selective induction of high-molecular-weight MAP-2.","date":"1990","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/2153774","citation_count":49,"is_preprint":false},{"pmid":"27577570","id":"PMC_27577570","title":"Mannan binding lectin-associated serine protease-2 (MASP-2) critically contributes to post-ischemic brain injury independent of MASP-1.","date":"2016","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/27577570","citation_count":48,"is_preprint":false},{"pmid":"32681658","id":"PMC_32681658","title":"MASP2 levels are elevated in thrombotic microangiopathies: association with microvascular endothelial cell injury and suppression by anti-MASP2 antibody narsoplimab.","date":"2020","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32681658","citation_count":48,"is_preprint":false},{"pmid":"9051273","id":"PMC_9051273","title":"Co-expression of MAP-2 and GFAP in cells developing from rat EGF responsive precursor cells.","date":"1997","source":"Brain research. Developmental brain research","url":"https://pubmed.ncbi.nlm.nih.gov/9051273","citation_count":48,"is_preprint":false},{"pmid":"16328467","id":"PMC_16328467","title":"Carbohydrate-binding specificities of mouse ficolin A, a splicing variant of ficolin A and ficolin B and their complex formation with MASP-2 and sMAP.","date":"2005","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/16328467","citation_count":47,"is_preprint":false},{"pmid":"21483710","id":"PMC_21483710","title":"Characterization of schistosome tegumental alkaline phosphatase (SmAP).","date":"2011","source":"PLoS neglected tropical diseases","url":"https://pubmed.ncbi.nlm.nih.gov/21483710","citation_count":46,"is_preprint":false},{"pmid":"7583214","id":"PMC_7583214","title":"Degradation of fodrin and MAP 2 after neonatal cerebral hypoxic-ischemia.","date":"1995","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/7583214","citation_count":46,"is_preprint":false},{"pmid":"8618422","id":"PMC_8618422","title":"Microtubule-associated protein 2 (MAP-2): a sensitive marker of seizure-related brain damage.","date":"1995","source":"Journal of neuroscience methods","url":"https://pubmed.ncbi.nlm.nih.gov/8618422","citation_count":46,"is_preprint":false},{"pmid":"2985613","id":"PMC_2985613","title":"Microheterogeneity of microtubule-associated proteins, MAP-1 and MAP-2, and differential phosphorylation of individual subcomponents.","date":"1985","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2985613","citation_count":46,"is_preprint":false},{"pmid":"20484373","id":"PMC_20484373","title":"SMAP-WS: a parallel web service for structural proteome-wide ligand-binding site comparison.","date":"2010","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/20484373","citation_count":44,"is_preprint":false},{"pmid":"25038892","id":"PMC_25038892","title":"Mannose-Binding Lectin (MBL) and MBL-associated serine protease-2 (MASP-2) in women with malignant and benign ovarian tumours.","date":"2014","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/25038892","citation_count":44,"is_preprint":false},{"pmid":"4055896","id":"PMC_4055896","title":"Analysis of the microtubule-binding domain of MAP-2.","date":"1985","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/4055896","citation_count":42,"is_preprint":false},{"pmid":"35509048","id":"PMC_35509048","title":"Cardio-facio-cutaneous syndrome and gastrointestinal defects: report on a newborn with 19p13.3 deletion including the MAP 2 K2 gene.","date":"2022","source":"Italian journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/35509048","citation_count":42,"is_preprint":false},{"pmid":"3089106","id":"PMC_3089106","title":"The binding of MAP-2 and tau on brain microtubules in vitro: implications for microtubule structure.","date":"1986","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/3089106","citation_count":40,"is_preprint":false},{"pmid":"25533914","id":"PMC_25533914","title":"Plasma levels of mannan-binding lectin-associated serine proteases MASP-1 and MASP-2 are elevated in type 1 diabetes and correlate with glycaemic control.","date":"2015","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25533914","citation_count":36,"is_preprint":false},{"pmid":"7836356","id":"PMC_7836356","title":"Non-cooperative binding of the MAP-2 microtubule-binding region to microtubules.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7836356","citation_count":34,"is_preprint":false},{"pmid":"39230905","id":"PMC_39230905","title":"Diagnostic Performance of GFAP, UCH-L1, and MAP-2 Within 30 and 60 Minutes of Traumatic Brain Injury.","date":"2024","source":"JAMA network open","url":"https://pubmed.ncbi.nlm.nih.gov/39230905","citation_count":34,"is_preprint":false},{"pmid":"12025943","id":"PMC_12025943","title":"MAP-2e, a novel MAP-2 isoform, is expressed in gliomas and delineates tumor architecture and patterns of infiltration.","date":"2002","source":"Journal of neuropathology and experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/12025943","citation_count":34,"is_preprint":false},{"pmid":"25359215","id":"PMC_25359215","title":"TFPI inhibits lectin pathway of complement activation by direct interaction with MASP-2.","date":"2014","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25359215","citation_count":33,"is_preprint":false},{"pmid":"1676984","id":"PMC_1676984","title":"Activation of MAP-2 kinase activity by the CD2 receptor in Jurkat T cells can be reversed by CD45 phosphatase.","date":"1991","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1676984","citation_count":33,"is_preprint":false},{"pmid":"11596488","id":"PMC_11596488","title":"Characterisation of microtubule-associated proteins at the synapse: absence of MAP 2.","date":"1983","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11596488","citation_count":31,"is_preprint":false},{"pmid":"25887173","id":"PMC_25887173","title":"Impact of MBL and MASP-2 gene polymorphism and its interaction on susceptibility to tuberculosis.","date":"2015","source":"BMC infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/25887173","citation_count":31,"is_preprint":false},{"pmid":"21843573","id":"PMC_21843573","title":"MASP2 gene polymorphism is associated with susceptibility to hepatitis C virus infection.","date":"2011","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21843573","citation_count":31,"is_preprint":false},{"pmid":"11045677","id":"PMC_11045677","title":"Systemic hypothermia following spinal cord compression injury in the rat: an immunohistochemical study on MAP 2 with special reference to dendrite changes.","date":"2000","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/11045677","citation_count":29,"is_preprint":false},{"pmid":"2481044","id":"PMC_2481044","title":"Sequence of a human MAP-2 region sharing epitopes with Alzheimer neurofibrillary tangles.","date":"1989","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/2481044","citation_count":28,"is_preprint":false},{"pmid":"15922870","id":"PMC_15922870","title":"Cloning, cellular localization, genomic organization, and tissue-specific expression of the TGFbeta1-inducible SMAP-5 gene.","date":"2005","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/15922870","citation_count":28,"is_preprint":false},{"pmid":"3293702","id":"PMC_3293702","title":"Microtubule-associated protein 2 (MAP 2) immunoreactivity in human fetal neocortex.","date":"1988","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/3293702","citation_count":28,"is_preprint":false},{"pmid":"9777418","id":"PMC_9777418","title":"MASP-2, the C3 convertase generating protease of the MBLectin complement activating pathway.","date":"1998","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/9777418","citation_count":27,"is_preprint":false},{"pmid":"19307021","id":"PMC_19307021","title":"Mannan-binding lectin-associated serine protease-2 (MASP-2) in a large cohort of neonates and its clinical associations.","date":"2009","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19307021","citation_count":27,"is_preprint":false},{"pmid":"15642466","id":"PMC_15642466","title":"Expression of SMAP-29 cathelicidin-like peptide in bacterial cells by intein-mediated system.","date":"2005","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/15642466","citation_count":27,"is_preprint":false},{"pmid":"10586086","id":"PMC_10586086","title":"The rat and mouse homologues of MASP-2 and MAp19, components of the lectin activation pathway of complement.","date":"1999","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/10586086","citation_count":26,"is_preprint":false},{"pmid":"18221301","id":"PMC_18221301","title":"MBL2 and MASP2 gene polymorphisms in patients with hepatocellular carcinoma.","date":"2008","source":"Journal of viral hepatitis","url":"https://pubmed.ncbi.nlm.nih.gov/18221301","citation_count":25,"is_preprint":false},{"pmid":"7438221","id":"PMC_7438221","title":"High molecular weight protein MAP 2 promoting microtubule assembly in vitro is associated with microtubules in cells.","date":"1980","source":"Cell biology international reports","url":"https://pubmed.ncbi.nlm.nih.gov/7438221","citation_count":25,"is_preprint":false},{"pmid":"11220628","id":"PMC_11220628","title":"Molecular cloning of the complement (C1r/C1s/MASP2-like serine proteases from the common carp (Cyprinus carpio).","date":"2001","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/11220628","citation_count":25,"is_preprint":false},{"pmid":"35878790","id":"PMC_35878790","title":"MASP-2 and MASP-3 inhibitors block complement activation, inflammation, and microvascular stasis in a murine model of vaso-occlusion in sickle cell disease.","date":"2022","source":"Translational research : the journal of laboratory and clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35878790","citation_count":25,"is_preprint":false},{"pmid":"9716519","id":"PMC_9716519","title":"cFKBP/SMAP; a novel molecule involved in the regulation of smooth muscle differentiation.","date":"1998","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9716519","citation_count":25,"is_preprint":false},{"pmid":"16029433","id":"PMC_16029433","title":"Novel MASP2 variants detected among North African and Sub-Saharan individuals.","date":"2005","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/16029433","citation_count":24,"is_preprint":false},{"pmid":"21198752","id":"PMC_21198752","title":"Mannan-binding lectin (MBL) and MBL-associated serine protease 2 (MASP-2) genotypes in colorectal cancer.","date":"2011","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21198752","citation_count":23,"is_preprint":false},{"pmid":"12605092","id":"PMC_12605092","title":"Diagnostic value of microtubule-associated protein-2 (MAP-2) for neuroendocrine neoplasms.","date":"2003","source":"Advances in anatomic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12605092","citation_count":23,"is_preprint":false},{"pmid":"31869396","id":"PMC_31869396","title":"Herpes simplex encephalitis in adult patients with MASP-2 deficiency.","date":"2019","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/31869396","citation_count":21,"is_preprint":false},{"pmid":"1331920","id":"PMC_1331920","title":"Dietary aluminum selectively decreases MAP-2 in brains of developing and adult rats.","date":"1992","source":"Neurotoxicology","url":"https://pubmed.ncbi.nlm.nih.gov/1331920","citation_count":21,"is_preprint":false},{"pmid":"2657503","id":"PMC_2657503","title":"Alz-50 immunoreactivity in the neonatal rat: changes in development and co-distribution with MAP-2 immunoreactivity.","date":"1989","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/2657503","citation_count":21,"is_preprint":false},{"pmid":"31828694","id":"PMC_31828694","title":"Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway.","date":"2019","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31828694","citation_count":20,"is_preprint":false},{"pmid":"29677125","id":"PMC_29677125","title":"Detrimental Effects of Helium Ion Irradiation on Cognitive Performance and Cortical Levels of MAP-2 in B6D2F1 Mice.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29677125","citation_count":20,"is_preprint":false},{"pmid":"23935922","id":"PMC_23935922","title":"Leprosy association with low MASP-2 levels generated by MASP2 haplotypes and polymorphisms flanking MAp19 exon 5.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23935922","citation_count":20,"is_preprint":false},{"pmid":"18455509","id":"PMC_18455509","title":"Association of Gap-43 (neuromodulin) with microtubule-associated protein MAP-2 in neuronal cells.","date":"2008","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/18455509","citation_count":20,"is_preprint":false},{"pmid":"22071314","id":"PMC_22071314","title":"Multiple domains of MASP-2, an initiating complement protease, are required for interaction with its substrate C4.","date":"2011","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22071314","citation_count":20,"is_preprint":false},{"pmid":"11922706","id":"PMC_11922706","title":"Microtubule-associated protein 2 (MAP-2) is expressed in low and high grade diffuse astrocytomas.","date":"2002","source":"Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia","url":"https://pubmed.ncbi.nlm.nih.gov/11922706","citation_count":20,"is_preprint":false},{"pmid":"7728337","id":"PMC_7728337","title":"Diminished expression of microtubule-associated protein (MAP-2) and beta-tubulin as a putative marker for ischemic injury in neocortical transplants.","date":"1995","source":"Cell transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/7728337","citation_count":20,"is_preprint":false},{"pmid":"33671334","id":"PMC_33671334","title":"Targeting the Complement Serine Protease MASP-2 as a Therapeutic Strategy for Coronavirus Infections.","date":"2021","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/33671334","citation_count":19,"is_preprint":false},{"pmid":"31154018","id":"PMC_31154018","title":"Schistosomes can hydrolyze proinflammatory and prothrombotic polyphosphate (polyP) via tegumental alkaline phosphatase, SmAP.","date":"2019","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/31154018","citation_count":19,"is_preprint":false},{"pmid":"17096357","id":"PMC_17096357","title":"Genetic influences on mannan-binding lectin (MBL) and mannan-binding lectin associated serine protease-2 (MASP-2) activity.","date":"2007","source":"Genetic epidemiology","url":"https://pubmed.ncbi.nlm.nih.gov/17096357","citation_count":19,"is_preprint":false},{"pmid":"21683108","id":"PMC_21683108","title":"Multiplex sequence-specific polymerase chain reaction reveals new MASP2 haplotypes associated with MASP-2 and MAp19 serum levels.","date":"2011","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21683108","citation_count":19,"is_preprint":false},{"pmid":"24221355","id":"PMC_24221355","title":"Bacterial killing mechanism of sheep myeloid antimicrobial peptide-18 (SMAP-18) and its Trp-substituted analog with improved cell selectivity and reduced mammalian cell toxicity.","date":"2013","source":"Amino acids","url":"https://pubmed.ncbi.nlm.nih.gov/24221355","citation_count":19,"is_preprint":false},{"pmid":"22380611","id":"PMC_22380611","title":"Mutations of complement lectin pathway genes MBL2 and MASP2 associated with placental malaria.","date":"2012","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/22380611","citation_count":18,"is_preprint":false},{"pmid":"19405982","id":"PMC_19405982","title":"Lack of association between polymorphisms of MASP2 and susceptibility to SARS coronavirus infection.","date":"2009","source":"BMC infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/19405982","citation_count":18,"is_preprint":false},{"pmid":"24424083","id":"PMC_24424083","title":"Dissociation and re-association studies on the interaction domains of mannan-binding lectin (MBL)-associated serine proteases, MASP-1 and MASP-2, provide evidence for heterodimer formation.","date":"2014","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24424083","citation_count":18,"is_preprint":false},{"pmid":"24094966","id":"PMC_24094966","title":"Calretinin and microtubule-associated protein-2 (MAP-2) immunohistochemistry in the diagnosis of Hirschsprung's disease.","date":"2013","source":"Journal of pediatric surgery","url":"https://pubmed.ncbi.nlm.nih.gov/24094966","citation_count":18,"is_preprint":false},{"pmid":"19363440","id":"PMC_19363440","title":"Utility of microtubule associated protein-2 (MAP-2) immunohistochemistry for identification of ganglion cells in paraffin-embedded rectal suction biopsies.","date":"2009","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19363440","citation_count":18,"is_preprint":false},{"pmid":"35139773","id":"PMC_35139773","title":"Methyltransferase-like (METTL)14-mediated N6-methyladenosine modification modulates retinal pigment epithelial (RPE) activity by regulating the methylation of microtubule-associated protein (MAP)2.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35139773","citation_count":17,"is_preprint":false},{"pmid":"27235854","id":"PMC_27235854","title":"Experimentally-induced anti-myeloperoxidase vasculitis does not require properdin, MASP-2 or bone marrow-derived C5.","date":"2016","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/27235854","citation_count":17,"is_preprint":false},{"pmid":"24390958","id":"PMC_24390958","title":"Overexpression of MAP-2 via formation of microtubules plays an important role in the sprouting of mossy fibers in epileptic rats.","date":"2014","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/24390958","citation_count":17,"is_preprint":false},{"pmid":"16805823","id":"PMC_16805823","title":"Involvement of a novel ADP-ribosylation factor GTPase-activating protein, SMAP, in membrane trafficking: implications in cancer cell biology.","date":"2006","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/16805823","citation_count":16,"is_preprint":false},{"pmid":"19775369","id":"PMC_19775369","title":"Genetic and structural analysis of MBL2 and MASP2 polymorphisms in south-eastern African children.","date":"2009","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/19775369","citation_count":16,"is_preprint":false},{"pmid":"9644265","id":"PMC_9644265","title":"Involvement of stromal membrane-associated protein (SMAP-1) in erythropoietic microenvironment.","date":"1998","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9644265","citation_count":16,"is_preprint":false},{"pmid":"25318078","id":"PMC_25318078","title":"Association of MASP2 polymorphisms and protein levels with rheumatic fever and rheumatic heart disease.","date":"2014","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25318078","citation_count":16,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49882,"output_tokens":4818,"usd":0.110958},"stage2":{"model":"claude-opus-4-6","input_tokens":8341,"output_tokens":3168,"usd":0.181358},"total_usd":0.292316,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"In normal human serum, MASP-2 activation strictly depends on MASP-1; MASP-1 acts as the exclusive activator of MASP-2, and inhibition of MASP-1 prevents autoactivation of MASP-2. Furthermore, MASP-1 produces 60% of C2a responsible for C3 convertase formation.\",\n      \"method\": \"Monospecific inhibitors against MASP-1 and MASP-2 used in functional complement activation assays in human serum\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — unique monospecific inhibitors with functional readouts, replicated mechanistic conclusion\",\n      \"pmids\": [\"22691502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MASP-2 is encoded by the MASP-2 gene and a truncated form (sMAP/MAp19) is produced by alternative polyadenylation using a sMAP-specific exon with an in-frame stop codon; MAp19 consists of the first two domains of MASP-2 (CUB1 and EGF-like) plus four additional C-terminal amino acids and is a component of the MBL-MASP complex.\",\n      \"method\": \"cDNA cloning, sequence analysis, and biochemical characterization of MBL-MASP complex components\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — molecular cloning with sequence validation; independently replicated across multiple labs\",\n      \"pmids\": [\"10330290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MASP-2 cleaves complement components C4 and C2 to form the C3 convertase C4b2a; its substrate specificity differs from MASP-1, with MASP-2 showing very low activity against fluorescent amide substrates but efficiently cleaving C4 as a natural protein substrate. C1-inhibitor inhibits both MASP-1 and MASP-2.\",\n      \"method\": \"In vitro cleavage assays using recombinant and serum-derived MASPs with fluorescent amide substrates and natural protein substrates; inhibitor profiling\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assays with recombinant proteins and defined substrates/inhibitors\",\n      \"pmids\": [\"14725788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MASP-2 substrate specificity requires P1 position and S2/S3 subsites (Gly at P2, hydrophobic at P3); MASP-2 is up to 1000 times more catalytically active than C1s toward C2, C4, and C1-inhibitor cleavage sequences; C1-inhibitor inhibits MASP-2 50-fold faster than C1s, identifying MASP-2 as a major physiological target of C1-inhibitor.\",\n      \"method\": \"Randomized substrate phage display library, peptide substrate cleavage assays, serpin inhibition kinetics\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with defined substrates and mutagenesis-level substrate profiling\",\n      \"pmids\": [\"17709141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"X-ray crystal structure of MAp19 (the alternative splice product of MASP-2) resolved to 2.5 Å reveals a head-to-tail homodimer stabilized by Ca2+ ions; point mutations at Tyr59, Asp60, Glu83, Asp105, Tyr106, and Glu109 in the CUB1 module abolish or strongly decrease interaction with MBL and L-ficolin, defining the common binding site.\",\n      \"method\": \"X-ray crystallography (2.5 Å resolution) and surface plasmon resonance with point mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with mutagenesis and SPR binding validation\",\n      \"pmids\": [\"15117939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"MASP-1, MASP-2, and MAp19 are found exclusively associated with MBL in serum (not with C1q); C1r and C1s associate exclusively with C1q (not MBL); the MASPs and MAp19 require both high salt and calcium chelation (EDTA) to fully dissociate from MBL; the bulk of MASP-1 and MAp19 circulates as large complexes not bound to MBL.\",\n      \"method\": \"Serum fractionation, gel-permeation chromatography, complement activation assays in C1r-deficient serum\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal association studies with multiple biochemical fractionation approaches\",\n      \"pmids\": [\"10878362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MAp19 does not compete with MASP-2 for binding to MBL at physiological concentrations, nor does it inhibit MASP-2-mediated complement activation; both MASP-2 and MAp19 are predominantly expressed in hepatocytes; high levels of MAp19 are found in urine where MASP-2 is absent.\",\n      \"method\": \"Quantitative ELISA with monoclonal antibodies, complement activation assays, immunohistochemistry, qRT-PCR\",\n      \"journal\": \"Journal of immunological methods\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods with quantitative assays correcting prior claims\",\n      \"pmids\": [\"21871896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MASP-1 cooperates with MASP-2 in generating the C3 convertase through the MBL pathway; depletion of MASP-1, MASP-2, and MASP-3 abolishes C3b deposition on mannan, and reconstitution with both MASP-1 and MASP-2 shows synergistic effect; MASP-3 inhibits this process; the cooperation requires C4 and C2 but not factor B.\",\n      \"method\": \"Complement depletion and reconstitution assays measuring C3b deposition on mannan-coated surfaces\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis-type reconstitution experiment with defined complement component depletions\",\n      \"pmids\": [\"17182967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MASP-1 and MASP-2 form heterodimeric co-complexes when bridged by MBL or ficolins; these co-complexes have a functional role in complement activation; MAp44 may inhibit complement by disrupting MASP-1–MASP-2 co-complexes and thereby impairing MASP-1-mediated transactivation of MASP-2.\",\n      \"method\": \"Native PAGE, size exclusion chromatography, complement activation assays, and inhibition studies with MAp44\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods demonstrating complex formation and functional consequences\",\n      \"pmids\": [\"23785123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MASP-2 requires multiple domains for high-affinity interaction with its substrate C4: the CCP1-CCP2-SP combination binds C4 with much higher affinity than CCP1-CCP2 or SP domain alone, indicating cooperative interaction; mutation of K342A in CCP1 abolishes binding to C4 and C4b.\",\n      \"method\": \"Binding assays with active and catalytically inactive recombinant MASP-2 domain constructs; site-directed mutagenesis\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding assays with domain deletion constructs and mutagenesis\",\n      \"pmids\": [\"22071314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Rat and mouse MASP-2 are components of the MBL lectin pathway activation complex; both MASP-2 and MAp19 are encoded by a single structural MASP-2 gene (as in humans) and are exclusively synthesized in the liver; rat MASP-2 cleaves complement component C4.\",\n      \"method\": \"cDNA cloning, Southern blot, PCR, hepatic biosynthesis demonstrated by tissue expression analysis, C4 cleavage assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — molecular cloning with functional C4 cleavage validation and tissue-specific expression\",\n      \"pmids\": [\"10586086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Carp MASP2 associates with MBL homologs and cleaves native human C4 into C4b (but not C4i with hydrolyzed thioester), demonstrating that MASP2 and its C4-cleaving function arose before the emergence of bony fish.\",\n      \"method\": \"Protein isolation, molecular cloning, phylogenetic analysis, C4 cleavage activity assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro functional assay in an ortholog, single study\",\n      \"pmids\": [\"17015733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MASP-2 critically mediates cerebral ischemia-reperfusion injury independently of MASP-1: MASP-2-deficient mice show significantly reduced neurological deficits, infarct volumes, C3 deposition, and pro-inflammatory microglia phenotype after transient ischemia, while MASP-1/3-deficient mice are not protected.\",\n      \"method\": \"Genetic knockout mice (MASP-2−/−, MASP-1/3−/−, fB−/−) and inhibitory antibody in tMCAO/3VO stroke models; immunohistochemistry, behavioral, and histopathological assessment\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific phenotypic readout, multiple orthogonal methods and genetic controls\",\n      \"pmids\": [\"27577570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Tissue factor pathway inhibitor (TFPI) selectively inhibits MASP-2 activity without affecting MASP-1 or classical pathway proteases C1s/C1r; the Kunitz-2 domain of TFPI is required for this inhibition, as demonstrated by domain-specific antibody blocking.\",\n      \"method\": \"Ex vivo lectin pathway C4-deposition assay, fluid-phase chromogenic MASP-2 activity assay, domain-specific monoclonal antibody blocking\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — functional assays with domain-specific antibodies establishing mechanism of inhibition\",\n      \"pmids\": [\"25359215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MASP-1 and MASP-2 CUB1-EGF-CUB2 fragments form Ca2+-dependent homodimers that can exchange subunits to form MASP-1:MASP-2 heterodimers after dissociation/re-association, providing structural basis for the co-complex formation required for transactivation.\",\n      \"method\": \"Size exclusion chromatography, native PAGE, EDTA dissociation and re-calcification reassociation experiments with recombinant domain fragments\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical reconstitution of heterodimer formation, single study\",\n      \"pmids\": [\"24424083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MASP-2 variants G634R and R203W in human patients cause functional defects including reduced (R203W) or abolished (G634R) protein secretion, loss of capability to cleave MASP-2 precursor into its active form (G634R), and reduced antiviral activity in vivo; MBL-deficient mice have decreased survival and increased HSV-1 brain burden, linking MASP-2 function to protection against herpes simplex encephalitis.\",\n      \"method\": \"In vitro expression of variant proteins assessing secretion and autoactivation cleavage; murine HSE model with MBL-deficient mice\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro functional characterization of variants plus in vivo mouse model, single lab\",\n      \"pmids\": [\"31869396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mouse ficolin A and its splicing variant, but not ficolin B, bind MASP-2 and form complexes with potent complement-activating capacity; sMAP (MAp19) competes with MASP-2 for association with ficolin A and inhibits complement activation by the ficolin A/MASP-2 complex, indicating a regulatory role for MAp19.\",\n      \"method\": \"Recombinant protein expression, binding assays, and complement activation assays\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — binding and functional assays with recombinant proteins, single lab\",\n      \"pmids\": [\"16328467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MASP-2 shares identical domain structure with MASP-1, MASP-3, C1r, and C1s (comprising CUB1-EGF-CUB2-CCP1-CCP2-serine protease domains); MASP-2 is the protease responsible for activating C4 and C2 to generate the C3 convertase C4bC2b; MASP-1 and MASP-3 are alternative splice products of the MASP1/3 gene, while MASP-2 and MAp19 are alternative products of the MASP-2 gene.\",\n      \"method\": \"Molecular cloning, sequence analysis, and functional complement assays\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicated across multiple labs, established domain organization and functional role\",\n      \"pmids\": [\"12396007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MASP-2 (the effector enzyme of the lectin pathway) is elevated in thrombotic microangiopathies; plasmas from TMA patients induce microvascular endothelial cell caspase 8 activation, which is suppressed by the anti-MASP-2 antibody narsoplimab, demonstrating that MASP-2-mediated lectin pathway activation directly contributes to endothelial injury in TMAs.\",\n      \"method\": \"ELISA for MASP-2 levels, in vitro MVEC caspase 8 activity assay with patient plasmas and narsoplimab inhibition\",\n      \"journal\": \"Clinical and experimental immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional in vitro assay with specific antibody inhibition and patient samples, single lab\",\n      \"pmids\": [\"32681658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MASP-2 and MASP-3 inhibitory monoclonal antibodies markedly reduce complement activation (Bb, C4d, C5a, complement deposition in liver/kidney/lung), hepatic inflammation markers (NF-κB, VCAM-1, ICAM-1, E-selectin), and microvascular stasis (vaso-occlusion) in sickle cell disease mice after hypoxia-reoxygenation or hemoglobin challenge.\",\n      \"method\": \"In vivo mouse model (Townes SS mice) with MASP-2 and MASP-3 inhibitory mAbs, intravital microscopy for microvascular stasis, ELISA and immunohistochemistry for complement markers\",\n      \"journal\": \"Translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO-equivalent antibody inhibition with specific phenotypic readouts, single lab\",\n      \"pmids\": [\"35878790\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MASP-2 is a serine protease of the lectin complement pathway that, upon activation exclusively by MASP-1 (which transactivates it within MBL/ficolin co-complexes), cleaves C4 and C2 to generate the C3 convertase C4bC2a; its catalytic activity is mediated by cooperative interactions of its CCP1-CCP2-SP domains with C4, is regulated primarily by C1-inhibitor (and also TFPI via its Kunitz-2 domain), and its alternative splice product MAp19 (sharing CUB1-EGF domains) circulates at comparable concentrations but does not significantly inhibit MASP-2 activity in vivo; MASP-2-dependent complement activation drives ischemia-reperfusion injury, thrombotic microangiopathies, and vaso-occlusion in sickle cell disease.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MASP-2 is the key effector serine protease of the lectin complement pathway, cleaving C4 and C2 to assemble the C3 convertase C4bC2a on pathogen surfaces and damaged host tissues. MASP-2 is exclusively activated by MASP-1 through transactivation within MBL- or ficolin-bridged heterodimeric co-complexes that form via Ca²⁺-dependent CUB1-EGF-CUB2 dimerization, and its catalytic engagement of C4 requires cooperative binding across the CCP1-CCP2-SP domains [PMID:22691502, PMID:23785123, PMID:22071314]. Its activity is regulated by C1-inhibitor, which inhibits MASP-2 50-fold faster than C1s, and by TFPI via its Kunitz-2 domain; an alternative splice product, MAp19, shares the CUB1-EGF domains but does not significantly inhibit MASP-2-dependent complement activation at physiological concentrations [PMID:17709141, PMID:25359215, PMID:21871896]. MASP-2-dependent lectin pathway activation drives ischemia-reperfusion injury in the brain and contributes to endothelial damage in thrombotic microangiopathies and vaso-occlusion in sickle cell disease [PMID:27577570, PMID:32681658, PMID:35878790].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Molecular cloning established that a single MASP-2 gene encodes both the full-length serine protease and a truncated splice variant (MAp19/sMAP) sharing CUB1-EGF domains, resolving the genetic origin and domain organization of the lectin pathway protease.\",\n      \"evidence\": \"cDNA cloning and sequence analysis in human, rat, and mouse with tissue expression profiling confirming liver-restricted synthesis\",\n      \"pmids\": [\"10330290\", \"10586086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulatory mechanisms controlling alternative splicing of MASP-2 vs. MAp19 not defined\", \"Post-translational processing steps not characterized\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The complete domain architecture of MASP-2 (CUB1-EGF-CUB2-CCP1-CCP2-SP) was mapped and its exclusive role in cleaving C4 and C2 to form the C3 convertase was confirmed, distinguishing it functionally from MASP-1 and MASP-3.\",\n      \"evidence\": \"Molecular cloning, sequence comparison with C1r/C1s family members, and functional complement assays\",\n      \"pmids\": [\"12396007\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for differential substrate recognition vs. C1s not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Enzymatic characterization defined MASP-2's substrate specificity—high activity toward native C4 but low activity on small fluorescent substrates—and identified C1-inhibitor as its physiological regulator, while crystal structure of MAp19 at 2.5 Å revealed the CUB1-domain residues critical for MBL/ficolin binding.\",\n      \"evidence\": \"In vitro cleavage assays with recombinant MASPs, serpin inhibition kinetics, X-ray crystallography of MAp19 with site-directed mutagenesis and SPR\",\n      \"pmids\": [\"14725788\", \"15117939\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length MASP-2 structure in complex with C4 not determined\", \"Whether MAp19 has an independent biological function beyond MBL binding remained open\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Reconstitution experiments demonstrated that MASP-1 and MASP-2 cooperate synergistically in C3 convertase generation through the lectin pathway, with MASP-3 acting as an inhibitor, establishing the functional hierarchy among MASPs.\",\n      \"evidence\": \"Complement depletion and reconstitution assays measuring C3b deposition on mannan-coated surfaces\",\n      \"pmids\": [\"17182967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MASP-1's role was direct activation of MASP-2 or parallel C2 cleavage was not yet distinguished\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Substrate phage display and kinetic analysis revealed that MASP-2 is up to 1000-fold more catalytically active than C1s toward C2 and C4 cleavage sequences, and that C1-inhibitor inhibits MASP-2 50-fold faster than C1s, redefining MASP-2 as the major physiological target of this serpin in complement regulation.\",\n      \"evidence\": \"Randomized substrate phage display, peptide cleavage assays, serpin inhibition kinetics\",\n      \"pmids\": [\"17709141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution of C1-inhibitor to MASP-2 regulation vs. other serpins not quantified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Domain-mapping experiments established that MASP-2's CCP1-CCP2-SP domains cooperate for high-affinity C4 binding and that K342 in CCP1 is essential, while quantitative serum measurements showed MAp19 does not inhibit MASP-2 complement activity at physiological concentrations, correcting prior claims.\",\n      \"evidence\": \"Binding assays with domain deletion constructs and site-directed mutagenesis; quantitative ELISA, complement activation assays, immunohistochemistry\",\n      \"pmids\": [\"22071314\", \"21871896\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full structural model of MASP-2–C4 interface not available\", \"Biological function of circulating and urinary MAp19 unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Using monospecific inhibitors in human serum, MASP-1 was identified as the exclusive physiological activator of MASP-2, resolving the long-standing question of whether MASP-2 can autoactivate in vivo.\",\n      \"evidence\": \"Monospecific MASP-1 and MASP-2 inhibitors in functional lectin pathway activation assays in normal human serum\",\n      \"pmids\": [\"22691502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MASP-2 can autoactivate under any non-physiological or pathological condition remains untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The structural basis for MASP-1–MASP-2 transactivation was elucidated: MBL/ficolins bridge Ca²⁺-dependent CUB1-EGF-CUB2 heterodimers that enable MASP-1 to directly cleave MASP-2, and MAp44 disrupts these co-complexes as an endogenous inhibitor.\",\n      \"evidence\": \"Native PAGE, SEC, Ca²⁺-dependent subunit exchange experiments, and complement activation assays with MAp44 inhibition\",\n      \"pmids\": [\"23785123\", \"24424083\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and architecture of native MBL-MASP co-complexes on target surfaces not resolved\", \"Quantitative contribution of MAp44 regulation in vivo not measured\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"TFPI was identified as a selective physiological inhibitor of MASP-2 that does not affect MASP-1 or classical pathway proteases, with the Kunitz-2 domain mediating this specificity—establishing a cross-talk mechanism between coagulation and lectin pathway regulation.\",\n      \"evidence\": \"Ex vivo C4-deposition assay, chromogenic MASP-2 activity assay, domain-specific monoclonal antibody blocking of TFPI\",\n      \"pmids\": [\"25359215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of TFPI–MASP-2 inhibition not validated in animal models\", \"Whether TFPI regulation of MASP-2 affects coagulation parameters not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"MASP-2 was demonstrated to be the critical driver of cerebral ischemia-reperfusion injury, as MASP-2-knockout mice showed reduced infarct volumes and neuroinflammation while MASP-1/3-knockout mice were unprotected, establishing a MASP-1-independent pathogenic role for MASP-2 in stroke.\",\n      \"evidence\": \"Genetic knockout mice (MASP-2⁻/⁻, MASP-1/3⁻/⁻) in tMCAO and 3VO stroke models with histopathological, immunohistochemical, and behavioral readouts\",\n      \"pmids\": [\"27577570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"MASP-1-independent activation mechanism of MASP-2 in this setting not explained\", \"Whether MASP-2 acts via C3 convertase or alternative substrates in neuroinflammation not distinguished\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Lectin pathway-dependent endothelial injury in thrombotic microangiopathies and sickle cell vaso-occlusion was shown to depend on MASP-2, as anti-MASP-2 antibodies suppressed caspase-8 activation in endothelial cells exposed to TMA plasmas and reduced complement deposition, inflammation, and microvascular stasis in sickle cell mice.\",\n      \"evidence\": \"In vitro MVEC caspase-8 assay with narsoplimab and patient plasmas; in vivo Townes SS mouse model with MASP-2 inhibitory mAbs, intravital microscopy, ELISA\",\n      \"pmids\": [\"32681658\", \"35878790\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling pathway from MASP-2 to endothelial caspase-8 not defined\", \"Clinical efficacy of MASP-2 inhibition in human TMA/SCD not established by these studies\", \"Single-lab findings for each disease model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the full structural basis of the MASP-2–C4 complex, the MASP-1-independent activation mechanism observed in ischemia-reperfusion, the biological function of MAp19, and whether MASP-2 cleaves non-complement substrates that contribute to its pathogenic roles.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of MASP-2 in complex with C4\", \"MAp19 function remains unknown\", \"Non-complement substrates of MASP-2 not systematically profiled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 3, 7, 9, 17]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [2, 3, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [5, 6, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 7, 8, 12, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 18, 19]}\n    ],\n    \"complexes\": [\n      \"MBL-MASP complex\",\n      \"Ficolin-MASP complex\"\n    ],\n    \"partners\": [\n      \"MASP1\",\n      \"MBL2\",\n      \"FCN1\",\n      \"FCN2\",\n      \"SERPING1\",\n      \"TFPI\",\n      \"C4\",\n      \"C2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}