{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:56:24Z","timestamp":1790272584108,"version":"4.1.0"},"reference-count":100,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T00:00:00Z","timestamp":1751587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01 NS095229"],"award-info":[{"award-number":["R01 NS095229"]}]},{"name":"NIH","award":["P30 CA177558"],"award-info":[{"award-number":["P30 CA177558"]}]},{"name":"NIH","award":["P30 CA177558"],"award-info":[{"award-number":["P30 CA177558"]}]},{"name":"University of Kentucky Markey Cancer Center","award":["R01 NS095229"],"award-info":[{"award-number":["R01 NS095229"]}]},{"name":"University of Kentucky Markey Cancer Center","award":["P30 CA177558"],"award-info":[{"award-number":["P30 CA177558"]}]},{"name":"University of Kentucky Markey Cancer Center","award":["P30 CA177558"],"award-info":[{"award-number":["P30 CA177558"]}]},{"name":"University of Kentucky Markey Cancer Center","award":["R01 NS095229"],"award-info":[{"award-number":["R01 NS095229"]}]},{"name":"University of Kentucky Markey Cancer Center","award":["P30 CA177558"],"award-info":[{"award-number":["P30 CA177558"]}]},{"name":"University of Kentucky Markey Cancer Center","award":["P30 CA177558"],"award-info":[{"award-number":["P30 CA177558"]}]},{"name":"University of Kentucky College of Medicine and Markey Cancer Center","award":["R01 NS095229"],"award-info":[{"award-number":["R01 NS095229"]}]},{"name":"University of Kentucky College of Medicine and Markey Cancer Center","award":["P30 CA177558"],"award-info":[{"award-number":["P30 CA177558"]}]},{"name":"University of Kentucky College of Medicine and Markey Cancer Center","award":["P30 CA177558"],"award-info":[{"award-number":["P30 CA177558"]}]},{"name":"University of Kentucky Markey Cancer Center","award":["R01 NS095229"],"award-info":[{"award-number":["R01 NS095229"]}]},{"name":"University of Kentucky Markey Cancer Center","award":["P30 CA177558"],"award-info":[{"award-number":["P30 CA177558"]}]},{"name":"University of Kentucky Markey Cancer Center","award":["P30 CA177558"],"award-info":[{"award-number":["P30 CA177558"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Calpain-5\/CAPN5 is a calcium-activated, non-lysosomal cysteine (thiol) protease. The substrate repertoire of CAPN5 is not known. Calpains catalyze limited proteolysis of their substrates, generating neo-N-termini that correspond to internal residues of their nascent substrate proteins. To identify such neo-N-termini generated by CAPN5, we employed an N-terminomics approach called TAILS (Terminal amine isotopic labeling of substrates) to quantitatively compare the N-terminal peptides detected in parental and CAPN5-deficient SH-SY5Y neuroblastoma cells. Thirty neo-N-termini corresponding to 29 protein groups and 24 unique proteins were detected to be depleted in the CAPN5\u2212\/\u2212 cells. A subset of the identified putative substrates was further studied with CAPN5 co-immunoprecipitation, in vitro calcium-induced CAPN5 proteolysis assay, and their cellular fragmentation patterns were compared in parental and CAPN5-deficient SH-SY5Y cells. Here, we provide evidence for CAPN5-mediated proteolysis of the synaptic proteins DLGAP4, IQSEC1 and MPDZ, the neurodegeneration-related EWS, hnRNPU, TFG and UGP2, the DNA replication regulator MCM3, and the neuronal differentiation regulator LMTK1. Our data provide new relevance for neovascular inflammatory vitreoretinopathy (NIV), a progressive eye disease caused by pathogenic mutations in CAPN5. Data are available via ProteomeXchange with identifier PXD064313.<\/jats:p>","DOI":"10.3390\/ijms26136459","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T08:58:23Z","timestamp":1751878703000},"page":"6459","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Identification of Proteolytic Substrates of Calpain-5 with N-Terminomics"],"prefix":"10.3390","volume":"26","author":[{"given":"Jozsef","family":"Gal","sequence":"first","affiliation":[{"name":"Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky, Lexington, KY 40536, USA"},{"name":"Department of Neuroscience, University of Kentucky, Lexington, KY 40536, USA"},{"name":"Department of Radiation Medicine, University of Kentucky, Lexington, KY 40536, USA"},{"name":"Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3429-4188","authenticated-orcid":false,"given":"Antoine","family":"Dufour","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada"},{"name":"Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada"},{"name":"Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eddy S.","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Radiation Medicine, University of Kentucky, Lexington, KY 40536, USA"},{"name":"Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James W.","family":"Geddes","sequence":"additional","affiliation":[{"name":"Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky, Lexington, KY 40536, USA"},{"name":"Department of Neuroscience, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1152\/physrev.00029.2002","article-title":"The calpain system","volume":"83","author":"Goll","year":"2003","journal-title":"Physiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1152\/physrev.1991.71.3.813","article-title":"Calcium-activated neutral protease (calpain) system: Structure, function, and regulation","volume":"71","author":"Croall","year":"1991","journal-title":"Physiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.bbapap.2011.08.005","article-title":"Calpains: An elaborate proteolytic system","volume":"1824","author":"Ono","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Kapilan, A., Bulluss, M., Ziegler, A.R., Dabaja, M., Derakhshani, A., Anowai, A., Armstrong, V., Campden, R., Young, D., and Sun, Y.J. (2025). N-terminomics and proteomics analysis of Calpain-2 reveal key proteolytic processing of metabolic and cell adhesion proteins. Protein Sci., 34.","DOI":"10.1002\/pro.70144"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1006\/geno.1997.4870","article-title":"A new subfamily of vertebrate calpains lacking a calmodulin-like domain: Implications for calpain regulation and evolution","volume":"45","author":"Dear","year":"1997","journal-title":"Genomics"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Bondada, V., Gal, J., Mashburn, C., Rodgers, D.W., Larochelle, K.E., Croall, D.E., and Geddes, J.W. (2021). The C2 domain of calpain 5 contributes to enzyme activation and membrane localization. Biochim. Biophys. Acta Mol. Cell Res., 1868.","DOI":"10.1016\/j.bbamcr.2021.119019"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"19383","DOI":"10.1074\/jbc.M114.575159","article-title":"Calpain 5 is highly expressed in the central nervous system (CNS), carries dual nuclear localization signals, and is associated with nuclear promyelocytic leukemia protein bodies","volume":"289","author":"Singh","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1167\/iovs.15-18680","article-title":"Calpain-5 Expression in the Retina Localizes to Photoreceptor Synapses","volume":"57","author":"Schaefer","year":"2016","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Chukai, Y., Iwamoto, T., Itoh, K., Tomita, H., and Ozaki, T. (2021). Characterization of mitochondrial calpain-5. Biochim. Biophys. Acta Mol. Cell Res., 1868.","DOI":"10.1016\/j.bbamcr.2021.118989"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Gal, J., Bondada, V., Mashburn, C.B., Rodgers, D.W., Croall, D.E., and Geddes, J.W. (2022). S-acylation regulates the membrane association and activity of Calpain-5. Biochim. Biophys. Acta Mol. Cell Res., 1869.","DOI":"10.1101\/2022.01.25.477766"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Geddes, J.W., Bondada, V., Croall, D.E., Rodgers, D.W., and Gal, J. (2023). Impaired activity and membrane association of most calpain-5 mutants causal for neovascular inflammatory vitreoretinopathy. Biochim. Biophys. Acta Mol. Basis Dis., 1869.","DOI":"10.1016\/j.bbadis.2023.166747"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Mahajan, V.B., Skeie, J.M., Bassuk, A.G., Fingert, J.H., Braun, T.A., Daggett, H.T., Folk, J.C., Sheffield, V.C., and Stone, E.M. (2012). Calpain-5 mutations cause autoimmune uveitis, retinal neovascularization, and photoreceptor degeneration. PLoS Genet., 8.","DOI":"10.1371\/journal.pgen.1003001"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4584","DOI":"10.1093\/hmg\/ddv189","article-title":"CAPN5 mutation in hereditary uveitis: The R243L mutation increases calpain catalytic activity and triggers intraocular inflammation in a mouse model","volume":"24","author":"Wert","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Velez, G., Bassuk, A.G., Schaefer, K.A., Brooks, B., Gakhar, L., Mahajan, M., Kahn, P., Tsang, S.H., Ferguson, P.J., and Mahajan, V.B. (2018). A novel de novo CAPN5 mutation in a patient with inflammatory vitreoretinopathy, hearing loss, and developmental delay. Cold Spring Harb. Mol. Case Stud., 4.","DOI":"10.1101\/mcs.a002519"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/j.celrep.2019.12.077","article-title":"Structural Insights into the Unique Activation Mechanisms of a Non-classical Calpain and Its Disease-Causing Variants","volume":"30","author":"Velez","year":"2020","journal-title":"Cell Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"20775","DOI":"10.1074\/jbc.M313873200","article-title":"On the sequential determinants of calpain cleavage","volume":"279","author":"Tompa","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1515\/hsz-2012-0143","article-title":"Understanding the substrate specificity of conventional calpains","volume":"393","author":"Sorimachi","year":"2012","journal-title":"Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1074\/mcp.M115.053413","article-title":"Predictions of Cleavability of Calpain Proteolysis by Quantitative Structure-Activity Relationship Analysis Using Newly Determined Cleavage Sites and Catalytic Efficiencies of an Oligopeptide Array","volume":"15","author":"Koyama","year":"2016","journal-title":"Mol. Cell. Proteom. MCP"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/978-1-4939-8988-1_11","article-title":"CalCleaveMKL: A Tool for Calpain Cleavage Prediction","volume":"1915","author":"duVerle","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1167\/iovs.17-22689","article-title":"Photoreceptor Cell-Derived CAPN5 Regulates Retinal Pigment Epithelium Cell Proliferation Through Direct Regulation of SLIT2 Cleavage","volume":"59","author":"Wang","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.bbrc.2022.03.156","article-title":"Mitochondrial calpain-5 truncates caspase-4 during endoplasmic reticulum stress","volume":"608","author":"Chukai","year":"2022","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_22","first-page":"3751","article-title":"Multiple neurotransmitter synthesis by human neuroblastoma cell lines and clones","volume":"38","author":"Biedler","year":"1978","journal-title":"Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/978-1-62703-640-5_2","article-title":"Considerations for the use of SH-SY5Y neuroblastoma cells in neurobiology","volume":"1078","author":"Kovalevich","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_24","first-page":"1086","article-title":"SH-SY5Y human neuroblastoma cell line: In vitro cell model of dopaminergic neurons in Parkinson\u2019s disease","volume":"123","author":"Xie","year":"2010","journal-title":"Chin. Med. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/nbt.1611","article-title":"Isotopic labeling of terminal amines in complex samples identifies protein N-termini and protease cleavage products","volume":"28","author":"Kleifeld","year":"2010","journal-title":"Nat. Biotechnol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1038\/nprot.2011.382","article-title":"Identifying and quantifying proteolytic events and the natural N terminome by terminal amine isotopic labeling of substrates","volume":"6","author":"Kleifeld","year":"2011","journal-title":"Nat. Protoc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1016\/j.cell.2013.08.021","article-title":"Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity","volume":"154","author":"Ran","year":"2013","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nmeth.2811","article-title":"BoxPlotR: A web tool for generation of box plots","volume":"11","author":"Spitzer","year":"2014","journal-title":"Nat. Methods"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zhou, Y., Zhou, B., Pache, L., Chang, M., Khodabakhshi, A.H., Tanaseichuk, O., Benner, C., and Chanda, S.K. (2019). Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat. Commun., 10.","DOI":"10.1038\/s41467-019-09234-6"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8157","DOI":"10.1073\/pnas.0901931106","article-title":"Proteomics analyses reveal the evolutionary conservation and divergence of N-terminal acetyltransferases from yeast and humans","volume":"106","author":"Arnesen","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1111\/j.1432-1033.1996.00173.x","article-title":"Sequence differences between human muscle and liver cDNAs for UDPglucose pyrophosphorylase and kinetic properties of the recombinant enzymes expressed in Escherichia coli","volume":"235","author":"Duggleby","year":"1996","journal-title":"Eur. J. Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1007\/s00401-019-02109-6","article-title":"Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases","volume":"139","author":"Perenthaler","year":"2020","journal-title":"Acta Neuropathol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Yin, X., Zeng, D., Liao, Y., Tang, C., and Li, Y. (2024). The Function of H2A Histone Variants and Their Roles in Diseases. Biomolecules, 14.","DOI":"10.3390\/biom14080993"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Wei, H., Zhang, Y., Jia, Y., Chen, X., Niu, T., Chatterjee, A., He, P., and Hou, G. (2024). Heat shock protein 90: Biological functions, diseases, and therapeutic targets. MedComm, 5.","DOI":"10.1002\/mco2.470"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.semcdb.2020.03.010","article-title":"RINGO\/Speedy proteins, a family of non-canonical activators of CDK1 and CDK2","volume":"107","author":"Gonzalez","year":"2020","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3835","DOI":"10.1007\/s00018-012-1050-1","article-title":"Evolution of the Cdk-activator Speedy\/RINGO in vertebrates","volume":"69","author":"Chauhan","year":"2012","journal-title":"Cell Mol. Life Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1146\/annurev-cellbio-030123-032748","article-title":"The Tubulin Code, from Molecules to Health and Disease","volume":"39","author":"McKenna","year":"2023","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1002\/humu.22747","article-title":"Gene conversion between cationic trypsinogen (PRSS1) and the pseudogene trypsinogen 6 (PRSS3P2) in patients with chronic pancreatitis","volume":"36","author":"Rygiel","year":"2015","journal-title":"Hum. Mutat."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1097\/00006676-200007000-00052","article-title":"Genes, cloned cDNAs, and proteins of human trypsinogens and pancreatitis-associated cationic trypsinogen mutations","volume":"21","author":"Chen","year":"2000","journal-title":"Pancreas"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Zha, C., Huang, A., Kailasam, S., Young, D., Dufour, A., and Sossin, W.S. (2025). Identifying putative substrates of Calpain-15 in neurodevelopment. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0319489"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Agbani, E.O., Young, D., Chen, S.A., Smith, S., Lee, A., Poole, A.W., Dufour, A., and Poon, M.C. (2023). Membrane procoagulation and N-terminomics\/TAILS profiling in Montreal platelet syndrome kindred with VWF p.V1316M mutation. Commun. Med., 3.","DOI":"10.1038\/s43856-023-00354-1"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Ameen, S.S., Griem-Krey, N., Dufour, A., Hossain, M.I., Hoque, A., Sturgeon, S., Nandurkar, H., Draxler, D.F., Medcalf, R.L., and Kamaruddin, M.A. (2023). N-Terminomic Changes in Neurons During Excitotoxicity Reveal Proteolytic Events Associated with Synaptic Dysfunctions and Potential Targets for Neuroprotection. Mol. Cell. Proteom. MCP, 22.","DOI":"10.1016\/j.mcpro.2023.100543"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Das, N., de Almeida, L.G.N., Derakhshani, A., Young, D., Mehdinejadiani, K., Salo, P., Rezansoff, A., Jay, G.D., Sommerhoff, C.P., and Schmidt, T.A. (2023). Tryptase beta regulation of joint lubrication and inflammation via proteoglycan-4 in osteoarthritis. Nat. Commun., 14.","DOI":"10.1038\/s41467-023-37598-3"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"E817","DOI":"10.1073\/pnas.1401639111","article-title":"Calpain-generated natural protein fragments as short-lived substrates of the N-end rule pathway","volume":"111","author":"Piatkov","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1136\/jmedgenet-2012-101294","article-title":"Mutation in MPDZ causes severe congenital hydrocephalus","volume":"50","author":"Tulbah","year":"2013","journal-title":"J. Med. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7432","DOI":"10.1167\/iovs.11-7872","article-title":"Mpdz null allele in an avian model of retinal degeneration and mutations in human leber congenital amaurosis and retinitis pigmentosa","volume":"52","author":"Ali","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/j.ajhg.2019.09.013","article-title":"Bi-allelic Variants in IQSEC1 Cause Intellectual Disability, Developmental Delay, and Short Stature","volume":"105","author":"Ansar","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1002\/gcc.20491","article-title":"EWSR1-CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytoma","volume":"46","author":"Antonescu","year":"2007","journal-title":"Genes. Chromosom. Cancer"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1136\/jmedgenet-2013-102102","article-title":"Truncating mutations in TAF4B and ZMYND15 causing recessive azoospermia","volume":"51","author":"Ayhan","year":"2014","journal-title":"J. Med. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5091","DOI":"10.1073\/pnas.1217197110","article-title":"Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure","volume":"110","author":"Beetz","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1056\/NEJMc032965","article-title":"A patient with two Ewing\u2019s sarcomas with distinct EWS fusion transcripts","volume":"350","author":"Bielack","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1038\/ng.2646","article-title":"Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1","volume":"45","author":"Carvill","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1159\/000468934","article-title":"Two Novel TEX15 Mutations in a Family with Nonobstructive Azoospermia","volume":"82","author":"Colombo","year":"2017","journal-title":"Gynecol. Obstet. Investig."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/359162a0","article-title":"Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours","volume":"359","author":"Delattre","year":"1992","journal-title":"Nature"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"4055","DOI":"10.1093\/hmg\/ddx296","article-title":"A TUBB6 mutation is associated with autosomal dominant non-progressive congenital facial palsy, bilateral ptosis and velopharyngeal dysfunction","volume":"26","author":"Fazeli","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1002\/gcc.20201","article-title":"Fusion of the EWSR1 and ATF1 genes without expression of the MITF-M transcript in angiomatoid fibrous histiocytoma","volume":"44","author":"Hallor","year":"2005","journal-title":"Genes Chromosom. Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Hamdan, F.F., Srour, M., Capo-Chichi, J.M., Daoud, H., Nassif, C., Patry, L., Massicotte, C., Ambalavanan, A., Spiegelman, D., and Diallo, O. (2014). De novo mutations in moderate or severe intellectual disability. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004772"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1002\/humu.23060","article-title":"Novel Genetic, Clinical, and Pathomechanistic Insights into TFG-Associated Hereditary Spastic Paraplegia","volume":"37","author":"Harlalka","year":"2016","journal-title":"Hum. Mutat."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.ajhg.2012.07.014","article-title":"The TRK-fused gene is mutated in hereditary motor and sensory neuropathy with proximal dominant involvement","volume":"91","author":"Ishiura","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_60","first-page":"1229","article-title":"A variant Ewing\u2019s sarcoma translocation (7;22) fuses the EWS gene to the ETS gene ETV1","volume":"10","author":"Jeon","year":"1995","journal-title":"Oncogene"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1111\/febs.13949","article-title":"The calcium-binding protein ALG-2 promotes endoplasmic reticulum exit site localization and polymerization of Trk-fused gene (TFG) protein","volume":"284","author":"Kanadome","year":"2017","journal-title":"FEBS J."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1007\/s00439-017-1814-7","article-title":"A recessive mutation in beta-IV-spectrin (SPTBN4) associates with congenital myopathy, neuropathy, and central deafness","volume":"136","author":"Knierim","year":"2017","journal-title":"Hum. Genet."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1016\/j.ajhg.2017.10.010","article-title":"Mutations in TUBB4B Cause a Distinctive Sensorineural Disease","volume":"101","author":"Luscan","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1038\/s41436-018-0138-x","article-title":"Autozygome and high throughput confirmation of disease genes candidacy","volume":"21","author":"Maddirevula","year":"2019","journal-title":"Genet. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"5581","DOI":"10.1093\/hmg\/ddv290","article-title":"Exome sequencing reveals a nonsense mutation in TEX15 causing spermatogenic failure in a Turkish family","volume":"24","author":"Okutman","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1038\/sj.onc.1200933","article-title":"A new member of the ETS family fused to EWS in Ewing tumors","volume":"14","author":"Peter","year":"1997","journal-title":"Oncogene"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1002\/ana.24964","article-title":"The genetic landscape of familial congenital hydrocephalus","volume":"81","author":"Shaheen","year":"2017","journal-title":"Ann. Neurol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1016\/j.ajhg.2022.02.003","article-title":"Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome","volume":"109","author":"Tessadori","year":"2022","journal-title":"Am. J. Hum. Genet."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1038\/ng.3956","article-title":"Germline mutations affecting the histone H4 core cause a developmental syndrome by altering DNA damage response and cell cycle control","volume":"49","author":"Tessadori","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/s41431-019-0552-9","article-title":"A de novo variant in the human HIST1H4J gene causes a syndrome analogous to the HIST1H4C-associated neurodevelopmental disorder","volume":"28","author":"Tessadori","year":"2020","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"101","DOI":"10.4103\/1008-682X.194998","article-title":"Case study of a patient with cryptozoospermia associated with a recessive TEX15 nonsense mutation","volume":"20","author":"Wang","year":"2018","journal-title":"Asian J. Androl."},{"key":"ref_72","unstructured":"Potz, B.A., Abid, M.R., and Sellke, F.W. (2016). Role of Calpain in Pathogenesis of Human Disease Processes. J. Nat. Sci., 2."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1007\/s12035-008-8036-x","article-title":"Calpain-mediated signaling mechanisms in neuronal injury and neurodegeneration","volume":"38","author":"Vosler","year":"2008","journal-title":"Mol. Neurobiol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1038\/nrc3050","article-title":"The calpain system and cancer","volume":"11","author":"Storr","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1093\/hmg\/1.9.685","article-title":"Genetic linkage of autosomal dominant neovascular inflammatory vitreoretinopathy to chromosome 11q13","volume":"1","author":"Stone","year":"1992","journal-title":"Hum. Mol. Genet."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1016\/S0161-6420(90)32447-8","article-title":"Autosomal dominant neovascular inflammatory vitreoretinopathy","volume":"97","author":"Bennett","year":"1990","journal-title":"Ophthalmology"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Bassuk, A.G., Yeh, S., Wu, S., Martin, D.F., Tsang, S.H., Gakhar, L., and Mahajan, V.B. (2015). Structural modeling of a novel CAPN5 mutation that causes uveitis and neovascular retinal detachment. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0122352"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1080\/09273948.2017.1370651","article-title":"Two Novel CAPN5 Variants Associated with Mild and Severe Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy Phenotypes","volume":"27","author":"Randazzo","year":"2019","journal-title":"Ocul. Immunol. Inflamm."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1002\/cne.23206","article-title":"Distinct synaptic localization patterns of brefeldin A-resistant guanine nucleotide exchange factors BRAG2 and BRAG3 in the mouse retina","volume":"521","author":"Sakagami","year":"2013","journal-title":"J. Comp. Neurol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"12974","DOI":"10.1074\/jbc.M008089200","article-title":"Interaction of serotonin 5-hydroxytryptamine type 2C receptors with PDZ10 of the multi-PDZ domain protein MUPP1","volume":"276","author":"Becamel","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/j.neuron.2004.08.003","article-title":"SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor-dependent synaptic AMPA receptor potentiation","volume":"43","author":"Krapivinsky","year":"2004","journal-title":"Neuron"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1093\/cercor\/bhac123","article-title":"Sapap4 deficiency leads to postsynaptic defects and abnormal behaviors relevant to hyperkinetic neuropsychiatric disorder in mice","volume":"33","author":"Wang","year":"2023","journal-title":"Cereb. Cortex"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2548","DOI":"10.1128\/MCB.00992-06","article-title":"Calpain 6 is involved in microtubule stabilization and cytoskeletal organization","volume":"27","author":"Tonami","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1021\/acs.biochem.9b00821","article-title":"N-Terminomics\/TAILS Profiling of Macrophages after Chemical Inhibition of Legumain","volume":"59","author":"Anderson","year":"2020","journal-title":"Biochemistry"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Ziegler, A.R., Dufour, A., Scott, N.E., and Edgington-Mitchell, L.E. (2024). Ion Mobility-Based Enrichment-Free N-Terminomics Analysis Reveals Novel Legumain Substrates in Murine Spleen. Mol. Cell. Proteom. MCP, 23.","DOI":"10.1016\/j.mcpro.2024.100714"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"5264","DOI":"10.1021\/acs.jproteome.1c00289","article-title":"Biochemical Tools for Tracking Proteolysis","volume":"20","author":"Wang","year":"2021","journal-title":"J. Proteome Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.tips.2019.11.008","article-title":"Proteomics and Imaging in Crohn\u2019s Disease: TAILS of Unlikely Allies","volume":"41","author":"Mainoli","year":"2020","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Jagdeo, J.M., Dufour, A., Klein, T., Solis, N., Kleifeld, O., Kizhakkedathu, J., Luo, H., Overall, C.M., and Jan, E. (2018). N-Terminomics TAILS Identifies Host Cell Substrates of Poliovirus and Coxsackievirus B3 3C Proteinases That Modulate Virus Infection. J. Virol., 92.","DOI":"10.1128\/JVI.02211-17"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"L1003","DOI":"10.1152\/ajplung.00175.2018","article-title":"TAILS proteomics reveals dynamic changes in airway proteolysis controlling protease activity and innate immunity during COPD exacerbations","volume":"315","author":"Dufour","year":"2018","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Bhardwaj, S., Bulluss, M., D\u2019Aubeterre, A., Derakhshani, A., Penner, R., Mahajan, M., Mahajan, V.B., and Dufour, A. (2024). Integrating the analysis of human biopsies using post-translational modifications proteomics. Protein Sci., 33.","DOI":"10.1002\/pro.4979"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/978-1-0716-2124-0_7","article-title":"N-Terminomics\/TAILS of Tissue and Liquid Biopsies","volume":"2456","author":"Anowai","year":"2022","journal-title":"Methods Mol. Biol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"D1539","DOI":"10.1093\/nar\/gkac1040","article-title":"The ProteomeXchange consortium at 10 years: 2023 update","volume":"51","author":"Deutsch","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"D543","DOI":"10.1093\/nar\/gkae1011","article-title":"The PRIDE database at 20 years: 2025 update","volume":"53","author":"Bandla","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1093\/abbs\/gmw107","article-title":"Construction of a series of pCS2+ backbone-based Gateway vectors for overexpressing various tagged proteins in vertebrates","volume":"48","author":"Wang","year":"2016","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2899","DOI":"10.1093\/hmg\/dds116","article-title":"Evaluating the role of the FUS\/TLS-related gene EWSR1 in amyotrophic lateral sclerosis","volume":"21","author":"Couthouis","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"D743","DOI":"10.1093\/nar\/gkp999","article-title":"Protein Structure Initiative Material Repository: An open shared public resource of structural genomics plasmids for the biological community","volume":"38","author":"Cormier","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s10969-011-9100-8","article-title":"PSI:Biology-materials repository: A biologist\u2019s resource for protein expression plasmids","volume":"12","author":"Cormier","year":"2011","journal-title":"J. Struct. Funct. Genom."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"D1253","DOI":"10.1093\/nar\/gkt1060","article-title":"DNASU plasmid and PSI:Biology-Materials repositories: Resources to accelerate biological research","volume":"42","author":"Seiler","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"D523","DOI":"10.1093\/nar\/gkac1052","article-title":"UniProt: The Universal Protein Knowledgebase in 2023","volume":"51","author":"UniProt","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Uhlen, M., Fagerberg, L., Hallstrom, B.M., Lindskog, C., Oksvold, P., Mardinoglu, A., Sivertsson, A., Kampf, C., Sjostedt, E., and Asplund, A. (2015). Proteomics. Tissue-based map of the human proteome. Science, 347.","DOI":"10.1126\/science.1260419"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/13\/6459\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:04:38Z","timestamp":1760033078000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/13\/6459"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,4]]},"references-count":100,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ijms26136459"],"URL":"https:\/\/doi.org\/10.3390\/ijms26136459","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,4]]}}}