{"gene":"CRTAP","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":2008,"finding":"CRTAP and P3H1 (encoded by LEPRE1) form a complex that performs prolyl 3-hydroxylation of Pro986 in the triple-helical domain of type I collagen α1(I) and type II collagen α1(II) chains, and brings cyclophilin-B (CYPB) to unfolded collagen.","method":"Biochemical analysis of patient fibroblasts with CRTAP/LEPRE1 mutations, collagen hydroxylation assays","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 2 — replicated across multiple labs with biochemical functional readouts and confirmed in patient cells","pmids":["18566967"],"is_preprint":false},{"year":2009,"finding":"CRTAP and P3H1 are mutually stabilized in the ER collagen prolyl 3-hydroxylation complex: null mutations in either gene lead to loss of both proteins at the protein level (but not mRNA level), proteasomal degradation accounts for part of P3H1 loss in CRTAP-null cells, and stable transfection of the missing cDNA restores both proteins and normalizes collagen helical modification.","method":"Western blot, immunofluorescence, stable transfection rescue, proteasomal inhibitor treatment, collagen modification assay in patient fibroblasts","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in a single study with functional rescue validation","pmids":["19846465"],"is_preprint":false},{"year":2009,"finding":"Loss of CRTAP in Crtap-/- mice abolishes prolyl 3-hydroxylation at Pro986 of α1(I) and α1(II) collagen chains and also of α2(V) chains, but does not affect 3-hydroxylation at two known 3Hyp sites in α1(IV) chains, indicating substrate specificity of the CRTAP/P3H1 complex for clade A fibrillar collagens.","method":"Mass spectrometry of collagen from Crtap-/- mouse tissues, histology, cellular proliferation assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — direct biochemical measurement in knockout animal model, replicated across tissues","pmids":["20485499"],"is_preprint":false},{"year":2009,"finding":"CRTAP deficiency leads to abnormally high bone matrix mineralization and altered mineralization kinetics in both Crtap-/- mice and OI type VII patients, indicating that CRTAP-dependent collagen modification is required for normal bone mineral density distribution.","method":"Quantitative backscattered electron imaging (qBEI) of bone mineral density distribution in Crtap-/- mice and patient bone biopsies","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 — direct measurement in KO mouse and patient tissue, single study","pmids":["19895918"],"is_preprint":false},{"year":2011,"finding":"CRTAP deficiency results in a severe deficiency (10–15% of control) of collagen deposited in extracellular matrix, with disorganized fibrillar networks and increased dermal collagen fibril diameters, due to defective matrix deposition rather than increased turnover, as shown by pulse-chase experiments.","method":"Immunofluorescence of long-term cultures, quantitative pulse-chase experiments, electron microscopy of dermal collagen fibrils in patient fibroblasts","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods, single lab","pmids":["21955071"],"is_preprint":false},{"year":1997,"finding":"Cartilage-associated protein (CASP/CRTAP) is expressed at very high levels in hypertrophic chondrocytes and localizes to the cartilage extracellular matrix in the developing chick embryo skeleton.","method":"Immunohistochemistry with specific antisera, Northern blot of chondrocyte differentiation stages","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 3 — direct localization experiment, single study, foundational characterization","pmids":["9217321"],"is_preprint":false},{"year":1999,"finding":"Mouse Crtap gene (mapped to chromosome 9F3-F4) encodes a protein expressed in all embryonic cartilages; the protein belongs to a novel family distinct from mammalian nuclear antigens despite sequence relatedness.","method":"cDNA cloning, immunohistochemistry, fluorescence in situ hybridization (FISH) for chromosomal mapping","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"Medium","confidence_rationale":"Tier 3 — direct localization by immunohistochemistry and chromosomal mapping","pmids":["10429950"],"is_preprint":false},{"year":2020,"finding":"In zebrafish crtap and p3h1 knockouts (which lack endogenous collagen type I 3-hydroxylation), loss of the CRTAP/P3H1 complex causes intracellular collagen type I overmodification, partial ER retention with enlarged ER cisternae, and disorganized extracellular collagen fibers with altered diameter, supporting that the primary function of the complex is as a collagen chaperone rather than solely for 3-hydroxylation.","method":"CRISPR/Cas9 knockout in zebrafish, electron microscopy, immunofluorescence, micro-CT, collagen biochemistry","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in genetic model organism with clean KO and defined cellular/structural phenotypes","pmids":["32173581"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of the P3H1/CRTAP/PPIB ternary complex reveal that the active sites of P3H1 and PPIB form a face-to-face bifunctional reaction center indicating coupled modification of collagen; CRTAP serves as a structural scaffold; multiple collagen-binding sites form a substrate interacting zone; a dual-ternary complex exists and its equilibrium is altered by mutations in the P3H1/PPIB active site or PPIB inhibitors.","method":"Cryo-EM structure determination, mutagenesis, PPIB inhibitor addition, biochemical assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure with mutagenesis and functional validation in a single rigorous study","pmids":["39245686"],"is_preprint":false},{"year":2023,"finding":"A deep intronic variant in CRTAP (c.794_1403A>G) introduces cryptic splice sites generating two mutant isoforms; both isoforms are unstable due to a 'GWxxI' degron, leading to loss of prolyl 3-hydroxylation and aggregation of type I collagen, with cell death by senescence.","method":"Genome sequencing, transcript analysis, protein stability assays, collagen hydroxylation assay, autophagy and senescence markers in patient cells","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 — multiple molecular methods linking mutation to protein instability and functional collagen defect, single study","pmids":["37146916"],"is_preprint":false},{"year":2021,"finding":"Loss of CRTAP in Crtap-/- mice results in thinner, weaker tendons with increased collagen cross-links, reduced collagen fibril size, altered tendon progenitor-like cell numbers, dysregulation of TGF-β and inflammatory signaling pathways, and severe motor impairments, demonstrating a role for CRTAP-dependent collagen modification in tendon integrity and motor function.","method":"Biomechanical testing, collagen cross-link analysis, electron microscopy, RNA-seq, immunohistochemistry, behavioral tests in Crtap-/- mouse model","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in genetic KO model with defined phenotypic readouts","pmids":["34036937"],"is_preprint":false},{"year":2015,"finding":"In-frame deletion affecting crucial amino acids in CRTAP leads to severely reduced CRTAP and P3H1 protein levels (though CRTAP transcript is normal) and decreased Pro986 3-hydroxylation, demonstrating that these residues are important for CRTAP/P3H1 complex interaction and/or stabilization.","method":"Western blot, transcript analysis, collagen 3-hydroxylation assay in patient fibroblasts","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 3 — mechanistic inference from patient mutation with biochemical functional readout, single lab","pmids":["21964860"],"is_preprint":false},{"year":2024,"finding":"Biallelic CRTAP mutations cause reduced CRTAP mRNA and absent CRTAP protein in osteoblasts, with significantly reduced prolyl 3-hydroxylation at Pro986 of the α1 chain of type I collagen, markedly reduced osteoid volume, decreased osteoblast numbers, and impaired active bone formation.","method":"Bone specimen analysis from OI patient, mRNA and protein quantification, prolyl 3-hydroxylation quantification in collagen from patient osteoblasts","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional study in patient-derived osteoblasts with multiple molecular readouts, single study","pmids":["38214665"],"is_preprint":false}],"current_model":"CRTAP (cartilage-associated protein) functions as an obligate scaffold subunit of the endoplasmic reticulum P3H1/CRTAP/PPIB ternary complex, which—as revealed by cryo-EM structures—positions the active sites of P3H1 and PPIB in a face-to-face bifunctional reaction center to catalyze coupled prolyl 3-hydroxylation (at Pro986) and cis-trans isomerization of type I, II, and V collagen α1 chains; CRTAP and P3H1 are mutually stabilized by proteasomal-dependent mechanisms, and loss of CRTAP abolishes collagen 3-hydroxylation, delays collagen helix folding causing overmodification, impairs collagen secretion and extracellular matrix deposition, and leads to the multi-systemic connective tissue disorder osteogenesis imperfecta type VII."},"narrative":{"teleology":[{"year":1997,"claim":"Identifying that CRTAP is a cartilage-expressed extracellular matrix protein in the developing skeleton established the gene's tissue context before any enzymatic function was known.","evidence":"Immunohistochemistry and Northern blot in chick embryo chondrocytes","pmids":["9217321"],"confidence":"Medium","gaps":["No enzymatic activity or binding partners identified","Only avian system examined","No functional perturbation performed"]},{"year":2008,"claim":"Demonstrating that the CRTAP/P3H1 complex performs prolyl 3-hydroxylation of Pro986 on type I and II collagen α1 chains and recruits cyclophilin B established the core enzymatic function of the complex and linked it to osteogenesis imperfecta.","evidence":"Collagen hydroxylation assays and biochemical analysis in fibroblasts from patients with CRTAP/LEPRE1 mutations","pmids":["18566967"],"confidence":"High","gaps":["Structural basis of complex assembly unknown","Relative contributions of 3-hydroxylation vs. chaperone activity unclear"]},{"year":2009,"claim":"Showing that CRTAP and P3H1 are mutually stabilized and that loss of either leads to proteasomal degradation of the other, with rescue by stable transfection, revealed the obligate nature of complex formation for protein stability and function.","evidence":"Western blot, immunofluorescence, proteasomal inhibitor treatment, and stable cDNA rescue in patient fibroblasts","pmids":["19846465"],"confidence":"High","gaps":["Specific interaction domains mediating mutual stabilization not mapped","Role of PPIB in complex stability not addressed"]},{"year":2009,"claim":"Mass spectrometry of Crtap-null mouse tissues demonstrated substrate specificity of the complex for clade A fibrillar collagens (types I, II, V) but not type IV collagen, defining the in vivo substrate repertoire and showing that CRTAP deficiency leads to abnormal bone mineralization.","evidence":"Mass spectrometry of collagen from Crtap−/− mouse tissues; quantitative backscattered electron imaging of bone mineral density in KO mice and patient biopsies","pmids":["20485499","19895918"],"confidence":"High","gaps":["Mechanism linking loss of 3-hydroxylation to hypermineralization unknown","Whether other P3H family members compensate for specific substrates not tested"]},{"year":2011,"claim":"Pulse-chase and electron microscopy experiments in CRTAP-deficient fibroblasts revealed that the primary matrix defect is severely impaired collagen deposition (not increased turnover), with disorganized fibrils of increased diameter, establishing the downstream cellular consequence.","evidence":"Quantitative pulse-chase, immunofluorescence of long-term cultures, electron microscopy of dermal collagen fibrils in patient fibroblasts","pmids":["21955071"],"confidence":"Medium","gaps":["Whether secretion rate or post-secretory assembly is the rate-limiting step not resolved","Single lab study"]},{"year":2020,"claim":"Zebrafish crtap and p3h1 knockouts, which naturally lack the 3-hydroxylation target site, still showed collagen overmodification, ER retention, and fibril disorganization, demonstrating that the complex functions as a collagen chaperone independently of its hydroxylase activity.","evidence":"CRISPR/Cas9 knockout in zebrafish with electron microscopy, immunofluorescence, micro-CT, and collagen biochemistry","pmids":["32173581"],"confidence":"High","gaps":["Chaperone mechanism (binding kinetics, substrate recognition) not characterized","Whether chaperone and hydroxylase functions are separable in mammalian systems not tested"]},{"year":2021,"claim":"Comprehensive analysis of Crtap-null mouse tendons revealed that CRTAP-dependent collagen modification is required for tendon biomechanical integrity and identified downstream dysregulation of TGF-β and inflammatory signaling, expanding the functional scope beyond bone.","evidence":"Biomechanical testing, collagen cross-link analysis, RNA-seq, electron microscopy, and behavioral tests in Crtap−/− mice","pmids":["34036937"],"confidence":"High","gaps":["Whether TGF-β pathway dysregulation is a direct consequence of altered collagen or secondary","Motor impairment contribution from tendon vs. bone vs. other tissues not dissected"]},{"year":2024,"claim":"Cryo-EM structures of the P3H1/CRTAP/PPIB ternary complex resolved the molecular architecture, showing CRTAP as a structural scaffold that orients P3H1 and PPIB active sites into a coupled bifunctional reaction center with a defined collagen substrate-binding zone.","evidence":"Cryo-EM structure determination with mutagenesis, inhibitor perturbation, and biochemical assays","pmids":["39245686"],"confidence":"High","gaps":["No structure of the complex bound to a collagen substrate peptide","Dual-ternary complex functional significance in vivo not established","Mechanism by which CRTAP scaffold allosterically influences catalysis not defined"]},{"year":null,"claim":"How the chaperone and hydroxylase activities of the complex are mechanistically coupled during collagen folding in the ER, and why loss of 3-hydroxylation at a single proline residue produces such severe skeletal and connective tissue phenotypes, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of complex engaged with collagen substrate","Relative contribution of chaperone vs. hydroxylase activity to disease pathogenesis not separated in mammalian models","No therapeutic rescue strategy validated in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[8]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[7,8]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,7,8]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[5,4]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,8]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[4,10]}],"complexes":["P3H1/CRTAP/PPIB (collagen prolyl 3-hydroxylation complex)"],"partners":["P3H1","PPIB"],"other_free_text":[]},"mechanistic_narrative":"CRTAP functions as an obligate structural scaffold within the endoplasmic reticulum-resident P3H1/CRTAP/PPIB ternary complex, which catalyzes prolyl 3-hydroxylation at Pro986 of fibrillar collagen α chains (types I, II, and V) coupled with peptidyl-prolyl cis-trans isomerization to facilitate proper collagen folding and secretion [PMID:18566967, PMID:39245686]. Cryo-EM structures demonstrate that CRTAP positions the P3H1 and PPIB active sites in a face-to-face bifunctional reaction center with multiple collagen-binding sites forming a substrate-interacting zone [PMID:39245686]. CRTAP and P3H1 are mutually stabilized through proteasome-dependent mechanisms, such that loss of either protein leads to degradation of the other and abolition of collagen 3-hydroxylation, resulting in collagen overmodification, ER retention, severely reduced extracellular matrix deposition, and abnormal collagen fibril architecture [PMID:19846465, PMID:32173581, PMID:21955071]. Biallelic loss-of-function mutations in CRTAP cause osteogenesis imperfecta type VII, characterized by defective bone formation, hypermineralization, and connective tissue fragility including tendon dysfunction [PMID:18566967, PMID:19895918, PMID:34036937]."},"prefetch_data":{"uniprot":{"accession":"O75718","full_name":"Cartilage-associated protein","aliases":[],"length_aa":401,"mass_kda":46.6,"function":"Necessary for efficient 3-hydroxylation of fibrillar collagen prolyl residues","subcellular_location":"Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/O75718/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CRTAP","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":[{"gene":"CPSF6","stoichiometry":10.0},{"gene":"SF3B4","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2},{"gene":"SNRPF","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CRTAP","total_profiled":1310},"omim":[{"mim_id":"615066","title":"OSTEOGENESIS IMPERFECTA, TYPE XIV; OI14","url":"https://www.omim.org/entry/615066"},{"mim_id":"610915","title":"OSTEOGENESIS IMPERFECTA, TYPE VIII; OI8","url":"https://www.omim.org/entry/610915"},{"mim_id":"610682","title":"OSTEOGENESIS IMPERFECTA, TYPE VII; OI7","url":"https://www.omim.org/entry/610682"},{"mim_id":"610339","title":"PROLYL 3-HYDROXYLASE 1; P3H1","url":"https://www.omim.org/entry/610339"},{"mim_id":"605497","title":"CARTILAGE-ASSOCIATED PROTEIN; CRTAP","url":"https://www.omim.org/entry/605497"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Intermediate filaments","reliability":"Approved"},{"location":"Actin filaments","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CRTAP"},"hgnc":{"alias_symbol":["CASP","LEPREL3","P3H5"],"prev_symbol":[]},"alphafold":{"accession":"O75718","domains":[{"cath_id":"1.25.40","chopping":"45-92_119-198","consensus_level":"medium","plddt":94.9923,"start":45,"end":198},{"cath_id":"-","chopping":"206-380","consensus_level":"high","plddt":95.257,"start":206,"end":380}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75718","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75718-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75718-F1-predicted_aligned_error_v6.png","plddt_mean":88.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CRTAP","jax_strain_url":"https://www.jax.org/strain/search?query=CRTAP"},"sequence":{"accession":"O75718","fasta_url":"https://rest.uniprot.org/uniprotkb/O75718.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75718/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75718"}},"corpus_meta":[{"pmid":"34533838","id":"PMC_34533838","title":"Critical assessment of methods of protein structure prediction (CASP)-Round XIV.","date":"2021","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/34533838","citation_count":353,"is_preprint":false},{"pmid":"10526365","id":"PMC_10526365","title":"Ab initio protein structure prediction of CASP III targets using ROSETTA.","date":"1999","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/10526365","citation_count":334,"is_preprint":false},{"pmid":"31589781","id":"PMC_31589781","title":"Critical assessment of methods of protein structure prediction (CASP)-Round XIII.","date":"2019","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/31589781","citation_count":317,"is_preprint":false},{"pmid":"24344053","id":"PMC_24344053","title":"Critical assessment of methods of protein structure prediction (CASP)--round x.","date":"2013","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/24344053","citation_count":272,"is_preprint":false},{"pmid":"12177301","id":"PMC_12177301","title":"Metallo-beta-lactamase fold within nucleic acids processing enzymes: the beta-CASP family.","date":"2002","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/12177301","citation_count":261,"is_preprint":false},{"pmid":"9271594","id":"PMC_9271594","title":"A CASP-8 mutation recognized by cytolytic T lymphocytes on a human head and neck carcinoma.","date":"1997","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/9271594","citation_count":252,"is_preprint":false},{"pmid":"14579342","id":"PMC_14579342","title":"Automated prediction of CASP-5 structures using the Robetta server.","date":"2003","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/14579342","citation_count":220,"is_preprint":false},{"pmid":"22361291","id":"PMC_22361291","title":"RNA-Puzzles: a CASP-like evaluation of RNA three-dimensional structure prediction.","date":"2012","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/22361291","citation_count":213,"is_preprint":false},{"pmid":"29082672","id":"PMC_29082672","title":"Critical assessment of methods of protein structure prediction (CASP)-Round XII.","date":"2017","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/29082672","citation_count":211,"is_preprint":false},{"pmid":"18566967","id":"PMC_18566967","title":"CRTAP and LEPRE1 mutations in recessive osteogenesis imperfecta.","date":"2008","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/18566967","citation_count":173,"is_preprint":false},{"pmid":"14579322","id":"PMC_14579322","title":"Critical assessment of methods of protein structure prediction (CASP)-round V.","date":"2003","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/14579322","citation_count":167,"is_preprint":false},{"pmid":"21997831","id":"PMC_21997831","title":"Critical assessment of methods of protein structure prediction (CASP)--round IX.","date":"2011","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/21997831","citation_count":145,"is_preprint":false},{"pmid":"16187365","id":"PMC_16187365","title":"Progress over the first decade of CASP experiments.","date":"2005","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/16187365","citation_count":135,"is_preprint":false},{"pmid":"9115219","id":"PMC_9115219","title":"Cleavage of PITSLRE kinases by ICE/CASP-1 and CPP32/CASP-3 during apoptosis induced by tumor necrosis factor.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9115219","citation_count":127,"is_preprint":false},{"pmid":"27122118","id":"PMC_27122118","title":"Prediction of homoprotein and heteroprotein complexes by protein docking and template-based modeling: A CASP-CAPRI experiment.","date":"2016","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/27122118","citation_count":124,"is_preprint":false},{"pmid":"16187341","id":"PMC_16187341","title":"Critical assessment of methods of protein structure prediction (CASP)--round 6.","date":"2005","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/16187341","citation_count":118,"is_preprint":false},{"pmid":"18086147","id":"PMC_18086147","title":"Melatonin maintains mitochondrial membrane potential and attenuates activation of initiator (casp-9) and effector caspases (casp-3/casp-7) and PARP in UVR-exposed HaCaT keratinocytes.","date":"2007","source":"Journal of pineal research","url":"https://pubmed.ncbi.nlm.nih.gov/18086147","citation_count":102,"is_preprint":false},{"pmid":"12429822","id":"PMC_12429822","title":"CASP, the alternatively spliced product of the gene encoding the CCAAT-displacement protein transcription factor, is a Golgi membrane protein related to giantin.","date":"2002","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/12429822","citation_count":102,"is_preprint":false},{"pmid":"37920879","id":"PMC_37920879","title":"Critical assessment of methods of protein structure prediction (CASP)-Round XV.","date":"2023","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/37920879","citation_count":93,"is_preprint":false},{"pmid":"19862557","id":"PMC_19862557","title":"Null mutations in LEPRE1 and CRTAP cause severe recessive osteogenesis imperfecta.","date":"2009","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/19862557","citation_count":84,"is_preprint":false},{"pmid":"28436943","id":"PMC_28436943","title":"Transient cell-specific EXO70A1 activity in the CASP domain and Casparian strip localization.","date":"2017","source":"Nature plants","url":"https://pubmed.ncbi.nlm.nih.gov/28436943","citation_count":82,"is_preprint":false},{"pmid":"33025508","id":"PMC_33025508","title":"Antidepressant Effect of Paeoniflorin Is Through Inhibiting Pyroptosis CASP-11/GSDMD Pathway.","date":"2020","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/33025508","citation_count":81,"is_preprint":false},{"pmid":"24038551","id":"PMC_24038551","title":"CASP prediction center infrastructure and evaluation measures in CASP10 and CASP ROLL.","date":"2013","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/24038551","citation_count":78,"is_preprint":false},{"pmid":"9671409","id":"PMC_9671409","title":"Upregulation of CASP genes in human tumor cells undergoing etoposide-induced apoptosis.","date":"1998","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9671409","citation_count":76,"is_preprint":false},{"pmid":"14744996","id":"PMC_14744996","title":"The metallo-beta-lactamase/beta-CASP domain of Artemis constitutes the catalytic core for V(D)J recombination.","date":"2004","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/14744996","citation_count":73,"is_preprint":false},{"pmid":"24150928","id":"PMC_24150928","title":"CASP10 results compared to those of previous CASP experiments.","date":"2013","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/24150928","citation_count":72,"is_preprint":false},{"pmid":"26716893","id":"PMC_26716893","title":"Sclerostin Antibody Treatment Improves the Bone Phenotype of Crtap(-/-) Mice, a Model of Recessive Osteogenesis Imperfecta.","date":"2016","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/26716893","citation_count":68,"is_preprint":false},{"pmid":"19846465","id":"PMC_19846465","title":"Prolyl 3-hydroxylase 1 and CRTAP are mutually stabilizing in the endoplasmic reticulum collagen prolyl 3-hydroxylation complex.","date":"2009","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19846465","citation_count":61,"is_preprint":false},{"pmid":"22445251","id":"PMC_22445251","title":"Hydrophobic poly (amino acid) modified PEI mediated delivery of rev-casp-3 for cancer therapy.","date":"2012","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/22445251","citation_count":57,"is_preprint":false},{"pmid":"19895918","id":"PMC_19895918","title":"CRTAP deficiency leads to abnormally high bone matrix mineralization in a murine model and in children with osteogenesis imperfecta type VII.","date":"2009","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/19895918","citation_count":56,"is_preprint":false},{"pmid":"20485499","id":"PMC_20485499","title":"Generalized connective tissue disease in Crtap-/- mouse.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20485499","citation_count":52,"is_preprint":false},{"pmid":"12052827","id":"PMC_12052827","title":"The N-terminal coiled coil domain of the cytohesin/ARNO family of guanine nucleotide exchange factors interacts with the scaffolding protein CASP.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12052827","citation_count":52,"is_preprint":false},{"pmid":"11835494","id":"PMC_11835494","title":"Comparison of performance in successive CASP experiments.","date":"2001","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/11835494","citation_count":52,"is_preprint":false},{"pmid":"23403287","id":"PMC_23403287","title":"Emergence of the β-CASP ribonucleases: highly conserved and ubiquitous metallo-enzymes involved in messenger RNA maturation and degradation.","date":"2013","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/23403287","citation_count":45,"is_preprint":false},{"pmid":"20375016","id":"PMC_20375016","title":"Euryarchaeal beta-CASP proteins with homology to bacterial RNase J Have 5'- to 3'-exoribonuclease activity.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20375016","citation_count":41,"is_preprint":false},{"pmid":"19550437","id":"PMC_19550437","title":"CRTAP mutations in lethal and severe osteogenesis imperfecta: the importance of combining biochemical and molecular genetic analysis.","date":"2009","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/19550437","citation_count":40,"is_preprint":false},{"pmid":"23222134","id":"PMC_23222134","title":"Archaeal β-CASP ribonucleases of the aCPSF1 family are orthologs of the eukaryal CPSF-73 factor.","date":"2012","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/23222134","citation_count":39,"is_preprint":false},{"pmid":"9332351","id":"PMC_9332351","title":"CASP, a novel, highly conserved alternative-splicing product of the CDP/cut/cux gene, lacks cut-repeat and homeo DNA-binding domains, and interacts with full-length CDP in vitro.","date":"1997","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/9332351","citation_count":37,"is_preprint":false},{"pmid":"20589633","id":"PMC_20589633","title":"Consistent refinement of submitted models at CASP using a knowledge-based potential.","date":"2010","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/20589633","citation_count":35,"is_preprint":false},{"pmid":"32682809","id":"PMC_32682809","title":"Pan-cancer analysis of the CASP gene family in relation to survival, tumor-infiltrating immune cells and therapeutic targets.","date":"2020","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/32682809","citation_count":34,"is_preprint":false},{"pmid":"32173581","id":"PMC_32173581","title":"Crtap and p3h1 knock out zebrafish support defective collagen chaperoning as the cause of their osteogenesis imperfecta phenotype.","date":"2020","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/32173581","citation_count":34,"is_preprint":false},{"pmid":"23725396","id":"PMC_23725396","title":"Analysis of association between IL-1β, CASP-9, and GDF5 variants and low-back pain in Chinese male soldier: clinical article.","date":"2013","source":"Journal of neurosurgery. Spine","url":"https://pubmed.ncbi.nlm.nih.gov/23725396","citation_count":29,"is_preprint":false},{"pmid":"21565697","id":"PMC_21565697","title":"Structure and activity of a novel archaeal β-CASP protein with N-terminal KH domains.","date":"2011","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/21565697","citation_count":27,"is_preprint":false},{"pmid":"17577583","id":"PMC_17577583","title":"Sorting nexin 27 interacts with the Cytohesin associated scaffolding protein (CASP) in lymphocytes.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17577583","citation_count":27,"is_preprint":false},{"pmid":"17618626","id":"PMC_17618626","title":"Proapoptotic histone H1.2 induces CASP-3 and -7 activation by forming a protein complex with CYT c, APAF-1 and CASP-9.","date":"2007","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/17618626","citation_count":27,"is_preprint":false},{"pmid":"19160091","id":"PMC_19160091","title":"Methylation patterns of Rb1 and Casp-8 promoters and their impact on their expression in bladder cancer.","date":"2009","source":"Cancer investigation","url":"https://pubmed.ncbi.nlm.nih.gov/19160091","citation_count":26,"is_preprint":false},{"pmid":"26756794","id":"PMC_26756794","title":"CASP 11 target classification.","date":"2016","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/26756794","citation_count":25,"is_preprint":false},{"pmid":"21955071","id":"PMC_21955071","title":"Deficiency of CRTAP in non-lethal recessive osteogenesis imperfecta reduces collagen deposition into matrix.","date":"2011","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21955071","citation_count":23,"is_preprint":false},{"pmid":"9217321","id":"PMC_9217321","title":"Cartilage associated protein (CASP) is a novel developmentally regulated chick embryo protein.","date":"1997","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/9217321","citation_count":23,"is_preprint":false},{"pmid":"29314274","id":"PMC_29314274","title":"Small angle X-ray scattering and cross-linking for data assisted protein structure prediction in CASP 12 with prospects for improved accuracy.","date":"2018","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/29314274","citation_count":23,"is_preprint":false},{"pmid":"29804017","id":"PMC_29804017","title":"Effect of the exogenous anthocyanin extract on key metabolic pathways and antioxidant status of Brazilian elodea (Egeria densa (Planch.) Casp.) exposed to cadmium and manganese.","date":"2018","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/29804017","citation_count":22,"is_preprint":false},{"pmid":"36959183","id":"PMC_36959183","title":"Directed growth and fusion of membrane-wall microdomains requires CASP-mediated inhibition and displacement of secretory foci.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36959183","citation_count":21,"is_preprint":false},{"pmid":"21964860","id":"PMC_21964860","title":"Severe osteogenesis imperfecta caused by a small in-frame deletion in CRTAP.","date":"2011","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/21964860","citation_count":20,"is_preprint":false},{"pmid":"34462960","id":"PMC_34462960","title":"Modeling SARS-CoV-2 proteins in the CASP-commons experiment.","date":"2021","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/34462960","citation_count":20,"is_preprint":false},{"pmid":"23765963","id":"PMC_23765963","title":"HuGE systematic review and meta-analysis demonstrate association of CASP-3 and CASP-7 genetic polymorphisms with cancer risk.","date":"2013","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/23765963","citation_count":20,"is_preprint":false},{"pmid":"19022407","id":"PMC_19022407","title":"A histidine in the beta-CASP domain of Artemis is critical for its full in vitro and in vivo functions.","date":"2008","source":"DNA repair","url":"https://pubmed.ncbi.nlm.nih.gov/19022407","citation_count":20,"is_preprint":false},{"pmid":"32030412","id":"PMC_32030412","title":"RNA processing machineries in Archaea: the 5'-3' exoribonuclease aRNase J of the β-CASP family is engaged specifically with the helicase ASH-Ski2 and the 3'-5' exoribonucleolytic RNA exosome machinery.","date":"2020","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/32030412","citation_count":20,"is_preprint":false},{"pmid":"24434518","id":"PMC_24434518","title":"Prostasin may contribute to chemoresistance, repress cancer cells in ovarian cancer, and is involved in the signaling pathways of CASP/PAK2-p34/actin.","date":"2014","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/24434518","citation_count":19,"is_preprint":false},{"pmid":"37146916","id":"PMC_37146916","title":"Deep intronic mutation in CRTAP results in unstable isoforms of the protein to induce type I collagen aggregation in a lethal type of osteogenesis imperfecta type VII.","date":"2023","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/37146916","citation_count":18,"is_preprint":false},{"pmid":"26054421","id":"PMC_26054421","title":"Universal RNA-degrading enzymes in Archaea: Prevalence, activities and functions of β-CASP ribonucleases.","date":"2015","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/26054421","citation_count":18,"is_preprint":false},{"pmid":"35176959","id":"PMC_35176959","title":"L-Carnitine alleviates hepatic and renal mitochondrial-dependent apoptotic progression induced by letrozole in female rats through modulation of Nrf-2, Cyt c and CASP-3 signaling.","date":"2022","source":"Drug and chemical toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/35176959","citation_count":18,"is_preprint":false},{"pmid":"10429950","id":"PMC_10429950","title":"cDNA cloning, characterization and chromosome mapping of Crtap encoding the mouse cartilage associated protein.","date":"1999","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/10429950","citation_count":18,"is_preprint":false},{"pmid":"32133710","id":"PMC_32133710","title":"Dental and craniofacial defects in the Crtap-/- mouse model of osteogenesis imperfecta type VII.","date":"2020","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/32133710","citation_count":17,"is_preprint":false},{"pmid":"25604815","id":"PMC_25604815","title":"CRTAP mutation in a patient with Cole-Carpenter syndrome.","date":"2015","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/25604815","citation_count":17,"is_preprint":false},{"pmid":"26634552","id":"PMC_26634552","title":"Mutational characterization of the P3H1/CRTAP/CypB complex in recessive osteogenesis imperfecta.","date":"2015","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/26634552","citation_count":16,"is_preprint":false},{"pmid":"12647401","id":"PMC_12647401","title":"CASP and CAFASP experiments and their findings.","date":"2003","source":"Methods of biochemical analysis","url":"https://pubmed.ncbi.nlm.nih.gov/12647401","citation_count":15,"is_preprint":false},{"pmid":"29117515","id":"PMC_29117515","title":"Metformin and epothilone A treatment up regulate pro-apoptotic PARP-1, Casp-3 and H2AX genes and decrease of AKT kinase level to control cell death of human hepatocellular carcinoma and ovary adenocarcinoma cells.","date":"2017","source":"Toxicology in vitro : an international journal published in association with BIBRA","url":"https://pubmed.ncbi.nlm.nih.gov/29117515","citation_count":15,"is_preprint":false},{"pmid":"34036937","id":"PMC_34036937","title":"Tendon and motor phenotypes in the Crtap mouse model of recessive osteogenesis imperfecta.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34036937","citation_count":14,"is_preprint":false},{"pmid":"35029147","id":"PMC_35029147","title":"CASP microdomain formation requires cross cell wall stabilization of domains and non-cell autonomous action of LOTR1.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/35029147","citation_count":14,"is_preprint":false},{"pmid":"23694935","id":"PMC_23694935","title":"Network properties of decoys and CASP predicted models: a comparison with native protein structures.","date":"2013","source":"Molecular bioSystems","url":"https://pubmed.ncbi.nlm.nih.gov/23694935","citation_count":13,"is_preprint":false},{"pmid":"19359048","id":"PMC_19359048","title":"CASP-9: A susceptibility locus for multiple sclerosis in Italy.","date":"2009","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/19359048","citation_count":13,"is_preprint":false},{"pmid":"28960539","id":"PMC_28960539","title":"Target highlights from the first post-PSI CASP experiment (CASP12, May-August 2016).","date":"2017","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/28960539","citation_count":12,"is_preprint":false},{"pmid":"22503789","id":"PMC_22503789","title":"DR2417, a hypothetical protein characterized as a novel β-CASP family nuclease in radiation resistant bacterium, Deinococcus radiodurans.","date":"2012","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/22503789","citation_count":12,"is_preprint":false},{"pmid":"24397429","id":"PMC_24397429","title":"Protein structure refinement of CASP target proteins using GNEIMO torsional dynamics method.","date":"2014","source":"Journal of chemical information and modeling","url":"https://pubmed.ncbi.nlm.nih.gov/24397429","citation_count":12,"is_preprint":false},{"pmid":"39245686","id":"PMC_39245686","title":"The structural basis for the collagen processing by human P3H1/CRTAP/PPIB ternary complex.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39245686","citation_count":11,"is_preprint":false},{"pmid":"19727905","id":"PMC_19727905","title":"Common variants in FLNB/CRTAP, not ARHGEF3 at 3p, are associated with osteoporosis in southern Chinese women.","date":"2009","source":"Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA","url":"https://pubmed.ncbi.nlm.nih.gov/19727905","citation_count":11,"is_preprint":false},{"pmid":"26758428","id":"PMC_26758428","title":"CASP 3 genetic polymorphisms and risk of Hepatocellular carcinoma: a case-control study in a Chinese population.","date":"2016","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26758428","citation_count":11,"is_preprint":false},{"pmid":"10702664","id":"PMC_10702664","title":"cDNA cloning, characterization and chromosome mapping of the gene encoding human cartilage associated protein (CRTAP).","date":"1999","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10702664","citation_count":11,"is_preprint":false},{"pmid":"28975675","id":"PMC_28975675","title":"Biological and functional relevance of CASP predictions.","date":"2017","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/28975675","citation_count":9,"is_preprint":false},{"pmid":"27149620","id":"PMC_27149620","title":"Estimation of Uncertainties in the Global Distance Test (GDT_TS) for CASP Models.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27149620","citation_count":9,"is_preprint":false},{"pmid":"23479148","id":"PMC_23479148","title":"Association between CASP-8 gene polymorphisms and cancer risk in some Asian population based on a HuGE review and meta-analysis.","date":"2013","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/23479148","citation_count":9,"is_preprint":false},{"pmid":"33165988","id":"PMC_33165988","title":"Tracking exogenous intracellular casp-3 using split GFP.","date":"2020","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/33165988","citation_count":8,"is_preprint":false},{"pmid":"18825161","id":"PMC_18825161","title":"Getting a GRASP on CASP: properties and role of the cytohesin-associated scaffolding protein in immunity.","date":"2008","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18825161","citation_count":8,"is_preprint":false},{"pmid":"23212337","id":"PMC_23212337","title":"Role of CASP-10 gene polymorphisms in cancer susceptibility: a HuGE review and meta-analysis.","date":"2012","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/23212337","citation_count":8,"is_preprint":false},{"pmid":"32922437","id":"PMC_32922437","title":"Novel Compound Heterozygous Mutations in CRTAP Cause Rare Autosomal Recessive Osteogenesis Imperfecta.","date":"2020","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32922437","citation_count":8,"is_preprint":false},{"pmid":"23479167","id":"PMC_23479167","title":"CASP-9 gene functional polymorphisms and cancer risk: a large-scale association study plus meta-analysis.","date":"2013","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/23479167","citation_count":8,"is_preprint":false},{"pmid":"23170140","id":"PMC_23170140","title":"CASP-8 -652 6N ins/del polymorphism and cancer risk: A literature-based systematic HuGE review and meta-analysis.","date":"2012","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23170140","citation_count":8,"is_preprint":false},{"pmid":"30043639","id":"PMC_30043639","title":"FOXA1 knock-out via CRISPR/Cas9 altered Casp-9, Bax, CCND1, CDK4, and fibronectin expressions in LNCaP cells.","date":"2018","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/30043639","citation_count":7,"is_preprint":false},{"pmid":"34551438","id":"PMC_34551438","title":"β-CASP proteins removing RNA polymerase from DNA: when a torpedo is needed to shoot a sitting duck.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/34551438","citation_count":6,"is_preprint":false},{"pmid":"37950210","id":"PMC_37950210","title":"Role of environmental specificity in CASP results.","date":"2023","source":"BMC bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/37950210","citation_count":6,"is_preprint":false},{"pmid":"26782454","id":"PMC_26782454","title":"Assessment of CASP gene polymorphisms in periodontal disease.","date":"2015","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/26782454","citation_count":6,"is_preprint":false},{"pmid":"38958645","id":"PMC_38958645","title":"Atramacronoid A induces the PANoptosis-like cell death of human breast cancer cells through the CASP-3/PARP-GSDMD-MLKL pathways.","date":"2024","source":"Journal of Asian natural products research","url":"https://pubmed.ncbi.nlm.nih.gov/38958645","citation_count":6,"is_preprint":false},{"pmid":"24648977","id":"PMC_24648977","title":"CASP-1, -2 and -5 gene polymorphisms and cancer risk: A review and meta-analysis.","date":"2013","source":"Biomedical reports","url":"https://pubmed.ncbi.nlm.nih.gov/24648977","citation_count":6,"is_preprint":false},{"pmid":"38214665","id":"PMC_38214665","title":"Genetic Analysis, Phenotypic Spectrum and Functional Study of Rare Osteogenesis Imperfecta Caused by CRTAP Variants.","date":"2024","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/38214665","citation_count":5,"is_preprint":false},{"pmid":"18600293","id":"PMC_18600293","title":"Gene duplication in early vertebrates results in tissue-specific subfunctionalized adaptor proteins: CASP and GRASP.","date":"2008","source":"Journal of molecular evolution","url":"https://pubmed.ncbi.nlm.nih.gov/18600293","citation_count":5,"is_preprint":false},{"pmid":"37584088","id":"PMC_37584088","title":"Açaí berry ameliorates cognitive impairment by inhibiting NLRP3/ASC/CASP axis in STZ-induced diabetic neuropathy in mice.","date":"2023","source":"Journal of neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/37584088","citation_count":5,"is_preprint":false},{"pmid":"35970273","id":"PMC_35970273","title":"Craniofacial and dental phenotype of two girls with osteogenesis imperfecta due to mutations in CRTAP.","date":"2022","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/35970273","citation_count":4,"is_preprint":false},{"pmid":"40890987","id":"PMC_40890987","title":"Updates to the CASP Infrastructure in 2024.","date":"2025","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/40890987","citation_count":4,"is_preprint":false},{"pmid":"25058460","id":"PMC_25058460","title":"Cytohesin-associated scaffolding protein (CASP) is involved in migration and IFN-γ secretion in natural killer cells.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/25058460","citation_count":4,"is_preprint":false},{"pmid":"23315881","id":"PMC_23315881","title":"A literature-based systematic HuGE review and meta-analysis show that CASP gene family polymorphisms are associated with risk of lung cancer.","date":"2013","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/23315881","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46270,"output_tokens":3042,"usd":0.09222},"stage2":{"model":"claude-opus-4-6","input_tokens":6440,"output_tokens":2256,"usd":0.1329},"total_usd":0.22512,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"CRTAP and P3H1 (encoded by LEPRE1) form a complex that performs prolyl 3-hydroxylation of Pro986 in the triple-helical domain of type I collagen α1(I) and type II collagen α1(II) chains, and brings cyclophilin-B (CYPB) to unfolded collagen.\",\n      \"method\": \"Biochemical analysis of patient fibroblasts with CRTAP/LEPRE1 mutations, collagen hydroxylation assays\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicated across multiple labs with biochemical functional readouts and confirmed in patient cells\",\n      \"pmids\": [\"18566967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CRTAP and P3H1 are mutually stabilized in the ER collagen prolyl 3-hydroxylation complex: null mutations in either gene lead to loss of both proteins at the protein level (but not mRNA level), proteasomal degradation accounts for part of P3H1 loss in CRTAP-null cells, and stable transfection of the missing cDNA restores both proteins and normalizes collagen helical modification.\",\n      \"method\": \"Western blot, immunofluorescence, stable transfection rescue, proteasomal inhibitor treatment, collagen modification assay in patient fibroblasts\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in a single study with functional rescue validation\",\n      \"pmids\": [\"19846465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Loss of CRTAP in Crtap-/- mice abolishes prolyl 3-hydroxylation at Pro986 of α1(I) and α1(II) collagen chains and also of α2(V) chains, but does not affect 3-hydroxylation at two known 3Hyp sites in α1(IV) chains, indicating substrate specificity of the CRTAP/P3H1 complex for clade A fibrillar collagens.\",\n      \"method\": \"Mass spectrometry of collagen from Crtap-/- mouse tissues, histology, cellular proliferation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical measurement in knockout animal model, replicated across tissues\",\n      \"pmids\": [\"20485499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CRTAP deficiency leads to abnormally high bone matrix mineralization and altered mineralization kinetics in both Crtap-/- mice and OI type VII patients, indicating that CRTAP-dependent collagen modification is required for normal bone mineral density distribution.\",\n      \"method\": \"Quantitative backscattered electron imaging (qBEI) of bone mineral density distribution in Crtap-/- mice and patient bone biopsies\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct measurement in KO mouse and patient tissue, single study\",\n      \"pmids\": [\"19895918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CRTAP deficiency results in a severe deficiency (10–15% of control) of collagen deposited in extracellular matrix, with disorganized fibrillar networks and increased dermal collagen fibril diameters, due to defective matrix deposition rather than increased turnover, as shown by pulse-chase experiments.\",\n      \"method\": \"Immunofluorescence of long-term cultures, quantitative pulse-chase experiments, electron microscopy of dermal collagen fibrils in patient fibroblasts\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, single lab\",\n      \"pmids\": [\"21955071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Cartilage-associated protein (CASP/CRTAP) is expressed at very high levels in hypertrophic chondrocytes and localizes to the cartilage extracellular matrix in the developing chick embryo skeleton.\",\n      \"method\": \"Immunohistochemistry with specific antisera, Northern blot of chondrocyte differentiation stages\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct localization experiment, single study, foundational characterization\",\n      \"pmids\": [\"9217321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Mouse Crtap gene (mapped to chromosome 9F3-F4) encodes a protein expressed in all embryonic cartilages; the protein belongs to a novel family distinct from mammalian nuclear antigens despite sequence relatedness.\",\n      \"method\": \"cDNA cloning, immunohistochemistry, fluorescence in situ hybridization (FISH) for chromosomal mapping\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct localization by immunohistochemistry and chromosomal mapping\",\n      \"pmids\": [\"10429950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In zebrafish crtap and p3h1 knockouts (which lack endogenous collagen type I 3-hydroxylation), loss of the CRTAP/P3H1 complex causes intracellular collagen type I overmodification, partial ER retention with enlarged ER cisternae, and disorganized extracellular collagen fibers with altered diameter, supporting that the primary function of the complex is as a collagen chaperone rather than solely for 3-hydroxylation.\",\n      \"method\": \"CRISPR/Cas9 knockout in zebrafish, electron microscopy, immunofluorescence, micro-CT, collagen biochemistry\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in genetic model organism with clean KO and defined cellular/structural phenotypes\",\n      \"pmids\": [\"32173581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of the P3H1/CRTAP/PPIB ternary complex reveal that the active sites of P3H1 and PPIB form a face-to-face bifunctional reaction center indicating coupled modification of collagen; CRTAP serves as a structural scaffold; multiple collagen-binding sites form a substrate interacting zone; a dual-ternary complex exists and its equilibrium is altered by mutations in the P3H1/PPIB active site or PPIB inhibitors.\",\n      \"method\": \"Cryo-EM structure determination, mutagenesis, PPIB inhibitor addition, biochemical assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure with mutagenesis and functional validation in a single rigorous study\",\n      \"pmids\": [\"39245686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A deep intronic variant in CRTAP (c.794_1403A>G) introduces cryptic splice sites generating two mutant isoforms; both isoforms are unstable due to a 'GWxxI' degron, leading to loss of prolyl 3-hydroxylation and aggregation of type I collagen, with cell death by senescence.\",\n      \"method\": \"Genome sequencing, transcript analysis, protein stability assays, collagen hydroxylation assay, autophagy and senescence markers in patient cells\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple molecular methods linking mutation to protein instability and functional collagen defect, single study\",\n      \"pmids\": [\"37146916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of CRTAP in Crtap-/- mice results in thinner, weaker tendons with increased collagen cross-links, reduced collagen fibril size, altered tendon progenitor-like cell numbers, dysregulation of TGF-β and inflammatory signaling pathways, and severe motor impairments, demonstrating a role for CRTAP-dependent collagen modification in tendon integrity and motor function.\",\n      \"method\": \"Biomechanical testing, collagen cross-link analysis, electron microscopy, RNA-seq, immunohistochemistry, behavioral tests in Crtap-/- mouse model\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in genetic KO model with defined phenotypic readouts\",\n      \"pmids\": [\"34036937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In-frame deletion affecting crucial amino acids in CRTAP leads to severely reduced CRTAP and P3H1 protein levels (though CRTAP transcript is normal) and decreased Pro986 3-hydroxylation, demonstrating that these residues are important for CRTAP/P3H1 complex interaction and/or stabilization.\",\n      \"method\": \"Western blot, transcript analysis, collagen 3-hydroxylation assay in patient fibroblasts\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic inference from patient mutation with biochemical functional readout, single lab\",\n      \"pmids\": [\"21964860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Biallelic CRTAP mutations cause reduced CRTAP mRNA and absent CRTAP protein in osteoblasts, with significantly reduced prolyl 3-hydroxylation at Pro986 of the α1 chain of type I collagen, markedly reduced osteoid volume, decreased osteoblast numbers, and impaired active bone formation.\",\n      \"method\": \"Bone specimen analysis from OI patient, mRNA and protein quantification, prolyl 3-hydroxylation quantification in collagen from patient osteoblasts\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional study in patient-derived osteoblasts with multiple molecular readouts, single study\",\n      \"pmids\": [\"38214665\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CRTAP (cartilage-associated protein) functions as an obligate scaffold subunit of the endoplasmic reticulum P3H1/CRTAP/PPIB ternary complex, which—as revealed by cryo-EM structures—positions the active sites of P3H1 and PPIB in a face-to-face bifunctional reaction center to catalyze coupled prolyl 3-hydroxylation (at Pro986) and cis-trans isomerization of type I, II, and V collagen α1 chains; CRTAP and P3H1 are mutually stabilized by proteasomal-dependent mechanisms, and loss of CRTAP abolishes collagen 3-hydroxylation, delays collagen helix folding causing overmodification, impairs collagen secretion and extracellular matrix deposition, and leads to the multi-systemic connective tissue disorder osteogenesis imperfecta type VII.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CRTAP functions as an obligate structural scaffold within the endoplasmic reticulum-resident P3H1/CRTAP/PPIB ternary complex, which catalyzes prolyl 3-hydroxylation at Pro986 of fibrillar collagen α chains (types I, II, and V) coupled with peptidyl-prolyl cis-trans isomerization to facilitate proper collagen folding and secretion [PMID:18566967, PMID:39245686]. Cryo-EM structures demonstrate that CRTAP positions the P3H1 and PPIB active sites in a face-to-face bifunctional reaction center with multiple collagen-binding sites forming a substrate-interacting zone [PMID:39245686]. CRTAP and P3H1 are mutually stabilized through proteasome-dependent mechanisms, such that loss of either protein leads to degradation of the other and abolition of collagen 3-hydroxylation, resulting in collagen overmodification, ER retention, severely reduced extracellular matrix deposition, and abnormal collagen fibril architecture [PMID:19846465, PMID:32173581, PMID:21955071]. Biallelic loss-of-function mutations in CRTAP cause osteogenesis imperfecta type VII, characterized by defective bone formation, hypermineralization, and connective tissue fragility including tendon dysfunction [PMID:18566967, PMID:19895918, PMID:34036937].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Identifying that CRTAP is a cartilage-expressed extracellular matrix protein in the developing skeleton established the gene's tissue context before any enzymatic function was known.\",\n      \"evidence\": \"Immunohistochemistry and Northern blot in chick embryo chondrocytes\",\n      \"pmids\": [\"9217321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No enzymatic activity or binding partners identified\", \"Only avian system examined\", \"No functional perturbation performed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that the CRTAP/P3H1 complex performs prolyl 3-hydroxylation of Pro986 on type I and II collagen α1 chains and recruits cyclophilin B established the core enzymatic function of the complex and linked it to osteogenesis imperfecta.\",\n      \"evidence\": \"Collagen hydroxylation assays and biochemical analysis in fibroblasts from patients with CRTAP/LEPRE1 mutations\",\n      \"pmids\": [\"18566967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of complex assembly unknown\", \"Relative contributions of 3-hydroxylation vs. chaperone activity unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showing that CRTAP and P3H1 are mutually stabilized and that loss of either leads to proteasomal degradation of the other, with rescue by stable transfection, revealed the obligate nature of complex formation for protein stability and function.\",\n      \"evidence\": \"Western blot, immunofluorescence, proteasomal inhibitor treatment, and stable cDNA rescue in patient fibroblasts\",\n      \"pmids\": [\"19846465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific interaction domains mediating mutual stabilization not mapped\", \"Role of PPIB in complex stability not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mass spectrometry of Crtap-null mouse tissues demonstrated substrate specificity of the complex for clade A fibrillar collagens (types I, II, V) but not type IV collagen, defining the in vivo substrate repertoire and showing that CRTAP deficiency leads to abnormal bone mineralization.\",\n      \"evidence\": \"Mass spectrometry of collagen from Crtap−/− mouse tissues; quantitative backscattered electron imaging of bone mineral density in KO mice and patient biopsies\",\n      \"pmids\": [\"20485499\", \"19895918\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking loss of 3-hydroxylation to hypermineralization unknown\", \"Whether other P3H family members compensate for specific substrates not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Pulse-chase and electron microscopy experiments in CRTAP-deficient fibroblasts revealed that the primary matrix defect is severely impaired collagen deposition (not increased turnover), with disorganized fibrils of increased diameter, establishing the downstream cellular consequence.\",\n      \"evidence\": \"Quantitative pulse-chase, immunofluorescence of long-term cultures, electron microscopy of dermal collagen fibrils in patient fibroblasts\",\n      \"pmids\": [\"21955071\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether secretion rate or post-secretory assembly is the rate-limiting step not resolved\", \"Single lab study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Zebrafish crtap and p3h1 knockouts, which naturally lack the 3-hydroxylation target site, still showed collagen overmodification, ER retention, and fibril disorganization, demonstrating that the complex functions as a collagen chaperone independently of its hydroxylase activity.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in zebrafish with electron microscopy, immunofluorescence, micro-CT, and collagen biochemistry\",\n      \"pmids\": [\"32173581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chaperone mechanism (binding kinetics, substrate recognition) not characterized\", \"Whether chaperone and hydroxylase functions are separable in mammalian systems not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Comprehensive analysis of Crtap-null mouse tendons revealed that CRTAP-dependent collagen modification is required for tendon biomechanical integrity and identified downstream dysregulation of TGF-β and inflammatory signaling, expanding the functional scope beyond bone.\",\n      \"evidence\": \"Biomechanical testing, collagen cross-link analysis, RNA-seq, electron microscopy, and behavioral tests in Crtap−/− mice\",\n      \"pmids\": [\"34036937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TGF-β pathway dysregulation is a direct consequence of altered collagen or secondary\", \"Motor impairment contribution from tendon vs. bone vs. other tissues not dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cryo-EM structures of the P3H1/CRTAP/PPIB ternary complex resolved the molecular architecture, showing CRTAP as a structural scaffold that orients P3H1 and PPIB active sites into a coupled bifunctional reaction center with a defined collagen substrate-binding zone.\",\n      \"evidence\": \"Cryo-EM structure determination with mutagenesis, inhibitor perturbation, and biochemical assays\",\n      \"pmids\": [\"39245686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the complex bound to a collagen substrate peptide\", \"Dual-ternary complex functional significance in vivo not established\", \"Mechanism by which CRTAP scaffold allosterically influences catalysis not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the chaperone and hydroxylase activities of the complex are mechanistically coupled during collagen folding in the ER, and why loss of 3-hydroxylation at a single proline residue produces such severe skeletal and connective tissue phenotypes, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of complex engaged with collagen substrate\", \"Relative contribution of chaperone vs. hydroxylase activity to disease pathogenesis not separated in mammalian models\", \"No therapeutic rescue strategy validated in vivo\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 7, 8]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [5, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [4, 10]}\n    ],\n    \"complexes\": [\n      \"P3H1/CRTAP/PPIB (collagen prolyl 3-hydroxylation complex)\"\n    ],\n    \"partners\": [\n      \"P3H1\",\n      \"PPIB\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}