{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T21:30:35Z","timestamp":1776979835233,"version":"3.51.4"},"reference-count":120,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2019,6,5]],"date-time":"2019-06-05T00:00:00Z","timestamp":1559692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Proteins containing Ly6\/uPAR (LU) domains exhibit very diverse biological functions and have broad taxonomic distributions in eukaryotes. In general, they adopt a characteristic three-fingered folding topology with three long loops projecting from a disulfide-rich globular core. The majority of the members of this protein domain family contain only a single LU domain, which can be secreted, glycolipid anchored, or constitute the extracellular ligand binding domain of type-I membrane proteins. Nonetheless, a few proteins contain multiple LU domains, for example, the urokinase receptor uPAR, C4.4A, and Haldisin. In the current review, we will discuss evolutionary aspects of this protein domain family with special emphasis on variations in their consensus disulfide bond patterns. Furthermore, we will present selected cases where missense mutations in LU domain\u2212containing proteins leads to dysfunctional proteins that are causally linked to genesis of human disease.<\/jats:p>","DOI":"10.3390\/ijms20112760","type":"journal-article","created":{"date-parts":[[2019,6,6]],"date-time":"2019-06-06T03:38:01Z","timestamp":1559792281000},"page":"2760","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Evolution and Medical Significance of LU Domain\u2212Containing Proteins"],"prefix":"10.3390","volume":"20","author":[{"given":"Julie Maja","family":"Leth","sequence":"first","affiliation":[{"name":"Finsen Laboratory, Ole Maaloes Vej 5, Righospitalet,  DK-2200 Copenhagen, Denmark"},{"name":"Biotechnology Research Innovation Centre (BRIC), Ole Maaloes Vej 5, University of Copenhagen,  DK-2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katrine Zinck","family":"Leth-Espensen","sequence":"additional","affiliation":[{"name":"Finsen Laboratory, Ole Maaloes Vej 5, Righospitalet,  DK-2200 Copenhagen, Denmark"},{"name":"Biotechnology Research Innovation Centre (BRIC), Ole Maaloes Vej 5, University of Copenhagen,  DK-2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3190-5411","authenticated-orcid":false,"given":"Kristian K\u00f8lby","family":"Kristensen","sequence":"additional","affiliation":[{"name":"Finsen Laboratory, Ole Maaloes Vej 5, Righospitalet,  DK-2200 Copenhagen, Denmark"},{"name":"Biotechnology Research Innovation Centre (BRIC), Ole Maaloes Vej 5, University of Copenhagen,  DK-2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8245-269X","authenticated-orcid":false,"given":"Anni","family":"Kumari","sequence":"additional","affiliation":[{"name":"Finsen Laboratory, Ole Maaloes Vej 5, Righospitalet,  DK-2200 Copenhagen, Denmark"},{"name":"Biotechnology Research Innovation Centre (BRIC), Ole Maaloes Vej 5, University of Copenhagen,  DK-2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5776-0989","authenticated-orcid":false,"given":"Anne-Marie","family":"Lund Winther","sequence":"additional","affiliation":[{"name":"Finsen Laboratory, Ole Maaloes Vej 5, Righospitalet,  DK-2200 Copenhagen, Denmark"},{"name":"Biotechnology Research Innovation Centre (BRIC), Ole Maaloes Vej 5, University of Copenhagen,  DK-2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen G.","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA"},{"name":"Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2215-4265","authenticated-orcid":false,"given":"Michael","family":"Ploug","sequence":"additional","affiliation":[{"name":"Finsen Laboratory, Ole Maaloes Vej 5, Righospitalet,  DK-2200 Copenhagen, Denmark"},{"name":"Biotechnology Research Innovation Centre (BRIC), Ole Maaloes Vej 5, University of Copenhagen,  DK-2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5064","DOI":"10.1111\/j.1742-4658.2005.04917.x","article-title":"Modules, multidomain proteins and organismic complexity","volume":"272","author":"Tordai","year":"2005","journal-title":"FEBS J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1042\/bst0311107","article-title":"Modular proteins at the cell surface","volume":"31","author":"Campbell","year":"2003","journal-title":"Biochem. Soc. Trans."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s40246-016-0074-2","article-title":"Organization, evolution and functions of the human and mouse Ly6\/uPAR family genes","volume":"10","author":"Loughner","year":"2016","journal-title":"Hum. Genom."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5441","DOI":"10.2741\/3092","article-title":"Structure and ligand interactions of the urokinase receptor (uPAR)","volume":"13","author":"Kjaergaard","year":"2008","journal-title":"Front. Biosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1730","DOI":"10.1093\/molbev\/msv052","article-title":"Multispecies Analysis of Expression Pattern Diversification in the Recently Expanded Insect Ly6 Gene Family","volume":"32","author":"Tanaka","year":"2015","journal-title":"Mol. Biol. Evol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2172","DOI":"10.3390\/toxins5112172","article-title":"Three-fingered RAVERs: Rapid Accumulation of Variations in Exposed Residues of snake venom toxins","volume":"5","author":"Sunagar","year":"2013","journal-title":"Toxins"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1073\/pnas.1817984116","article-title":"Structure of the lipoprotein lipase-GPIHBP1 complex that mediates plasma triglyceride hydrolysis","volume":"116","author":"Birrane","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1111\/jnc.13975","article-title":"The three-finger toxin fold: A multifunctional structural scaffold able to modulate cholinergic functions","volume":"142","author":"Kessler","year":"2017","journal-title":"J. Neurochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/s41421-018-0026-1","article-title":"Cryo-EM structure of the ASIC1a-mambalgin-1 complex reveals that the peptide toxin mambalgin-1 inhibits acid-sensing ion channels through an unusual allosteric effect","volume":"4","author":"Sun","year":"2018","journal-title":"Cell Discov."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"27313","DOI":"10.1074\/jbc.M112.377960","article-title":"Specificity and structure of a high affinity activin receptor-like kinase 1 (ALK1) signaling complex","volume":"287","author":"Townson","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Chalmers, I.W., Fitzsimmons, C.M., Brown, M., Pierrot, C., Jones, F.M., Wawrzyniak, J.M., Fernandez-Fuentes, N., Tukahebwa, E.M., Dunne, D.W., and Khalife, J. (2015). Human IgG1 Responses to Surface Localised Schistosoma mansoni Ly6 Family Members Drop following Praziquantel Treatment. PLoS Negl. Trop. Dis., 9.","DOI":"10.1371\/journal.pntd.0003920"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1107\/S0907444907015557","article-title":"Crystal structure of CD59: Implications for molecular recognition of the complement proteins C8 and C9 in the membrane-attack complex","volume":"63","author":"Huang","year":"2007","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"10618","DOI":"10.1074\/jbc.M110.189100","article-title":"NMR structure and action on nicotinic acetylcholine receptors of water-soluble domain of human LYNX1","volume":"286","author":"Lyukmanova","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1107\/S0907444900011501","article-title":"The atomic resolution structure of bucandin, a novel toxin isolated from the Malayan krait, determined by direct methods","volume":"56","author":"Kuhn","year":"2000","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2026","DOI":"10.1021\/acs.jcim.5b00322","article-title":"Multidimensional Drift of Sequence Attributes and Functional Profiles in the Superfamily of the Three-Finger Proteins and Their Structural Homologues","volume":"55","author":"Galat","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"jeb198556","DOI":"10.1242\/jeb.198556","article-title":"Injury affects coelomic fluid proteome of the common starfish, Asterias rubens","volume":"222","author":"Shabelnikov","year":"2019","journal-title":"J. Exp. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1096\/fj.08-113555","article-title":"Irditoxin, a novel covalently linked heterodimeric three-finger toxin with high taxon-specific neurotoxicity","volume":"23","author":"Pawlak","year":"2009","journal-title":"FASEB J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1093\/molbev\/msq194","article-title":"Disulfide bond acquisition through eukaryotic protein evolution","volume":"28","author":"Wong","year":"2011","journal-title":"Mol. Biol. Evol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Dashevsky, D., Debono, J., Rokyta, D., Nouwens, A., Josh, P., and Fry, B.G. (2018). Three-Finger Toxin Diversification in the Venoms of Cat-Eye Snakes (Colubridae: Boiga). J. Mol. Evol.","DOI":"10.1007\/s00239-018-9864-6"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8302","DOI":"10.1074\/jbc.M109.074161","article-title":"Structural and functional characterization of a novel homodimeric three-finger neurotoxin from the venom of Ophiophagus hannah (king cobra)","volume":"285","author":"Roy","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/nature11494","article-title":"Black mamba venom peptides target acid-sensing ion channels to abolish pain","volume":"490","author":"Diochot","year":"2012","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"29030","DOI":"10.1074\/jbc.M605850200","article-title":"Denmotoxin, a three-finger toxin from the colubrid snake Boiga dendrophila (Mangrove Catsnake) with bird-specific activity","volume":"281","author":"Pawlak","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1872","DOI":"10.1002\/pro.2169","article-title":"Dynamics and functional differences between dendroaspin and rhodostomin: Insights into protein scaffolds in integrin recognition","volume":"21","author":"Cheng","year":"2012","journal-title":"Protein Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0896-6273(01)00461-5","article-title":"The binding site of acetylcholine receptor as visualized in the X-Ray structure of a complex between alpha-bungarotoxin and a mimotope peptide","volume":"32","author":"Harel","year":"2001","journal-title":"Neuron"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13147","DOI":"10.1021\/bi00248a026","article-title":"Crystal Structure of.kappa.-Bungarotoxin at 2.3-.ANG. Resolution","volume":"33","author":"Dewan","year":"1994","journal-title":"Biochemistry"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1101\/gr.3228405","article-title":"From genome to \u201cvenome\u201d: Molecular origin and evolution of the snake venom proteome inferred from phylogenetic analysis of toxin sequences and related body proteins","volume":"15","author":"Fry","year":"2005","journal-title":"Genome Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1038\/ncomms2065","article-title":"Dynamic evolution of venom proteins in squamate reptiles","volume":"3","author":"Casewell","year":"2012","journal-title":"Nat. Commun"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"20651","DOI":"10.1073\/pnas.1314702110","article-title":"The king cobra genome reveals dynamic gene evolution and adaptation in the snake venom system","volume":"110","author":"Vonk","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1126\/science.1195320","article-title":"Lynx1, a cholinergic brake, limits plasticity in adult visual cortex","volume":"330","author":"Morishita","year":"2010","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.neuron.2006.07.025","article-title":"The prototoxin lynx1 acts on nicotinic acetylcholine receptors to balance neuronal activity and survival in vivo","volume":"51","author":"Miwa","year":"2006","journal-title":"Neuron"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Lyukmanova, E.N., Shulepko, M.A., Kudryavtsev, D., Bychkov, M.L., Kulbatskii, D.S., Kasheverov, I.E., Astapova, M.V., Feofanov, A.V., Thomsen, M.S., and Mikkelsen, J.D. (2016). Human Secreted Ly-6\/uPAR Related Protein-1 (SLURP-1) Is a Selective Allosteric Antagonist of alpha7 Nicotinic Acetylcholine Receptor. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0149733"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.neuron.2004.07.015","article-title":"Tethering naturally occurring peptide toxins for cell-autonomous modulation of ion channels and receptors in vivo","volume":"43","author":"Wen","year":"2004","journal-title":"Neuron"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2199","DOI":"10.1242\/dev.033845","article-title":"Boudin is required for septate junction organisation in Drosophila and codes for a diffusible protein of the Ly6 superfamily","volume":"136","author":"Hijazi","year":"2009","journal-title":"Development"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3132","DOI":"10.1093\/molbev\/msx237","article-title":"Diverse Cis-Regulatory Mechanisms Contribute to Expression Evolution of Tandem Gene Duplicates","volume":"34","author":"Santos","year":"2017","journal-title":"Mol. Biol. Evol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.1242\/dev.052605","article-title":"Crooked, coiled and crimpled are three Ly6-like proteins required for proper localization of septate junction components","volume":"137","author":"Nilton","year":"2010","journal-title":"Development"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Tempesta, C., Hijazi, A., Moussian, B., and Roch, F. (2017). Boudin trafficking reveals the dynamic internalisation of specific septate junction components in Drosophila. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0185897"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e01473","DOI":"10.7554\/eLife.01473","article-title":"Identification of Redeye, a new sleep-regulating protein whose expression is modulated by sleep amount","volume":"3","author":"Shi","year":"2014","journal-title":"eLife"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/nn.2454","article-title":"SLEEPLESS, a Ly-6\/neurotoxin family member, regulates the levels, localization and activity of Shaker","volume":"13","author":"Wu","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.cub.2014.02.026","article-title":"SLEEPLESS is a bifunctional regulator of excitability and cholinergic synaptic transmission","volume":"24","author":"Wu","year":"2014","journal-title":"Curr. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"8111","DOI":"10.1073\/pnas.1222166110","article-title":"Expression of TEX101, regulated by ACE, is essential for the production of fertile mouse spermatozoa","volume":"110","author":"Fujihara","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1126\/science.aat7113","article-title":"The Ly6\/uPAR protein Bouncer is necessary and sufficient for species-specific fertilization","volume":"361","author":"Herberg","year":"2018","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1007\/s10142-015-0449-9","article-title":"Identification and expression of an uncharacterized Ly-6 gene cluster in zebrafish Danio rerio","volume":"15","author":"Guo","year":"2015","journal-title":"Funct. Integr. Genom."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.gene.2017.11.062","article-title":"Involvement of Lypge in the formation of eye and pineal gland in zebrafish","volume":"642","author":"Ji","year":"2018","journal-title":"Gene"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/s00427-012-0393-9","article-title":"Identification and expression of a novel member of Ly-6 superfamily in zebrafish Denio rerio","volume":"222","author":"Ji","year":"2012","journal-title":"Dev. Genes Evol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.devcel.2013.07.020","article-title":"Lypd6 enhances Wnt\/beta-catenin signaling by promoting Lrp6 phosphorylation in raft plasma membrane domains","volume":"26","author":"Ozhan","year":"2013","journal-title":"Dev. Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s40257-015-0157-1","article-title":"Mal de Meleda: A Focused Review","volume":"17","author":"Perez","year":"2016","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/sj.jid.5700551","article-title":"SLURP1 is a late marker of epidermal differentiation and is absent in Mal de Meleda","volume":"127","author":"Favre","year":"2007","journal-title":"J. Investig. Dermatol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1111\/bjd.13868","article-title":"Heterogeneity in the properties of mutant secreted lymphocyte antigen 6\/urokinase receptor-related protein 1 (SLURP1) in Mal de Meleda","volume":"173","author":"Adeyo","year":"2015","journal-title":"Br. J. Dermatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1038\/jid.2014.19","article-title":"Palmoplantar keratoderma along with neuromuscular and metabolic phenotypes in Slurp1-deficient mice","volume":"134","author":"Adeyo","year":"2014","journal-title":"J. Investig. Dermatol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.jid.2015.11.003","article-title":"Palmoplantar Keratoderma in Slurp2-Deficient Mice","volume":"136","author":"Allan","year":"2016","journal-title":"J. Investig. Dermatol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.jdermsci.2017.08.014","article-title":"Palmoplantar keratoderma in Slurp1\/Slurp2 double-knockout mice","volume":"89","author":"Allan","year":"2018","journal-title":"J. Dermatol. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"30698","DOI":"10.1038\/srep30698","article-title":"Secreted Isoform of Human Lynx1 (SLURP-2): Spatial Structure and Pharmacology of Interactions with Different Types of Acetylcholine Receptors","volume":"6","author":"Lyukmanova","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"327","DOI":"10.4049\/jimmunol.1701238","article-title":"Absence of CD59 in Guinea Pigs: Analysis of the Cavia porcellus Genome Suggests the Evolution of a CD59 Pseudogene","volume":"200","author":"Boshra","year":"2018","journal-title":"J. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1182\/blood-2012-07-441857","article-title":"CD59 deficiency is associated with chronic hemolysis and childhood relapsing immune-mediated polyneuropathy","volume":"121","author":"Nevo","year":"2013","journal-title":"Blood"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1053\/j.seminhematol.2018.04.004","article-title":"Congenital Defects in the Expression of the Glycosylphosphatidylinositol-Anchored Complement Regulatory Proteins CD59 and Decay-Accelerating Factor","volume":"55","author":"Kinoshita","year":"2018","journal-title":"Semin. Hematol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.thromres.2018.06.006","article-title":"Prothrombotic mechanisms in patients with congenital p.Cys89Tyr mutation in CD59","volume":"168","author":"Tabib","year":"2018","journal-title":"Thromb. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e280","DOI":"10.1212\/NXG.0000000000000280","article-title":"Molecular pathogenesis of human CD59 deficiency","volume":"4","author":"Karbian","year":"2018","journal-title":"Neurol. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3707","DOI":"10.1182\/blood.V99.10.3707","article-title":"Crry, but not CD59 and DAF, is indispensable for murine erythrocyte protection in vivo from spontaneous complement attack","volume":"99","author":"Miwa","year":"2002","journal-title":"Blood"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S0896-6273(00)80757-6","article-title":"lynx1, an endogenous toxin-like modulator of nicotinic acetylcholine receptors in the mammalian CNS","volume":"23","author":"Miwa","year":"1999","journal-title":"Neuron"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/S0896-6273(02)00632-3","article-title":"Novel modulation of neuronal nicotinic acetylcholine receptors by association with the endogenous prototoxin lynx1","volume":"33","author":"Miwa","year":"2002","journal-title":"Neuron"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Miwa, J.M., and Walz, A. (2012). Enhancement in motor learning through genetic manipulation of the Lynx1 gene. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0043302"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1096\/fj.201600733R","article-title":"Isoform-specific mechanisms of alpha3beta4*-nicotinic acetylcholine receptor modulation by the prototoxin lynx1","volume":"31","author":"George","year":"2017","journal-title":"FASEB J."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1111\/jnc.13718","article-title":"Functional interaction between Lypd6 and nicotinic acetylcholine receptors","volume":"138","author":"Arvaniti","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.tips.2014.11.003","article-title":"Three-finger snake neurotoxins and Ly6 proteins targeting nicotinic acetylcholine receptors: Pharmacological tools and endogenous modulators","volume":"36","author":"Tsetlin","year":"2015","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"He, C., Hu, X., Jung, R.S., Larsson, M., Tu, Y., Duarte-Vogel, S., Kim, P., Sandoval, N.P., Price, T.R., and Allan, C.M. (2017). Lipoprotein lipase reaches the capillary lumen in chickens despite an apparent absence of GPIHBP1. JCI Insight, 2.","DOI":"10.1172\/jci.insight.96783"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/j.tem.2016.04.013","article-title":"GPIHBP1 and Plasma Triglyceride Metabolism","volume":"27","author":"Fong","year":"2016","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.cmet.2010.04.016","article-title":"GPIHBP1 is responsible for the entry of lipoprotein lipase into capillaries","volume":"12","author":"Davies","year":"2010","journal-title":"Cell Metab."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/j.cmet.2014.01.017","article-title":"The GPIHBP1-LPL complex is responsible for the margination of triglyceride-rich lipoproteins in capillaries","volume":"19","author":"Goulbourne","year":"2014","journal-title":"Cell Metab."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"E6020","DOI":"10.1073\/pnas.1806774115","article-title":"A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine regulates lipoprotein lipase","volume":"115","author":"Kristensen","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e12095","DOI":"10.7554\/eLife.12095","article-title":"The acidic domain of the endothelial membrane protein GPIHBP1 stabilizes lipoprotein lipase activity by preventing unfolding of its catalytic domain","volume":"5","author":"Mysling","year":"2016","journal-title":"eLife"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Mysling, S., Kristensen, K.K., Larsson, M., Kovrov, O., Bensadouen, A., Jorgensen, T.J., Olivecrona, G., Young, S.G., and Ploug, M. (2016). The angiopoietin-like protein ANGPTL4 catalyzes unfolding of the hydrolase domain in lipoprotein lipase and the endothelial membrane protein GPIHBP1 counteracts this unfolding. eLife, 5.","DOI":"10.7554\/eLife.20958.015"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s13205-011-0026-4","article-title":"Comparative studies of glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1: Evidence for a eutherian mammalian origin for the GPIHBP1 gene from an LY6-like gene","volume":"2","author":"Holmes","year":"2012","journal-title":"3 Biotech"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1002\/mrd.1080410115","article-title":"Characterization of alternatively spliced human SP-10 mRNAs","volume":"41","author":"Freemerman","year":"1995","journal-title":"Mol. Reprod. Dev."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1016\/j.jacl.2016.03.009","article-title":"Clinical and genetic features of 3 patients with familial chylomicronemia due to mutations in GPIHBP1 gene","volume":"10","author":"Rabacchi","year":"2016","journal-title":"J. Clin. Lipidol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.jacl.2015.12.015","article-title":"Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency","volume":"10","author":"Rodrigues","year":"2016","journal-title":"J. Clin. Lipidol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"19491","DOI":"10.1074\/jbc.M114.558528","article-title":"Multimerization of glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) and familial chylomicronemia from a serine-to-cysteine substitution in GPIHBP1 Ly6 domain","volume":"289","author":"Plengpanich","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1161\/CIRCRESAHA.116.305085","article-title":"GPIHBP1 missense mutations often cause multimerization of GPIHBP1 and thereby prevent lipoprotein lipase binding","volume":"116","author":"Beigneux","year":"2015","journal-title":"Circ. Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1056\/NEJMoa1611930","article-title":"Autoantibodies against GPIHBP1 as a Cause of Hypertriglyceridemia","volume":"376","author":"Beigneux","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1016\/j.jacl.2017.05.017","article-title":"GPIHBP1 autoantibodies in a patient with unexplained chylomicronemia","volume":"11","author":"Hu","year":"2017","journal-title":"J. Clin. Lipidol"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4246","DOI":"10.1073\/pnas.1720032115","article-title":"Flavivirus internalization is regulated by a size-dependent endocytic pathway","volume":"115","author":"Hackett","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3961","DOI":"10.1038\/s41598-018-22040-2","article-title":"Deletion of the Syncytin A receptor Ly6e impairs syncytiotrophoblast fusion and placental morphogenesis causing embryonic lethality in mice","volume":"8","author":"Langford","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Bacquin, A., Bireau, C., Tanguy, M., Romanet, C., Vernochet, C., Dupressoir, A., and Heidmann, T. (2017). A Cell Fusion-Based Screening Method Identifies Glycosylphosphatidylinositol-Anchored Protein Ly6e as the Receptor for Mouse Endogenous Retroviral Envelope Syncytin-A. J. Virol., 91.","DOI":"10.1128\/JVI.00832-17"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.2174\/1381612033454630","article-title":"Structure-function relationships in the interaction between the urokinase-type plasminogen activator and its receptor","volume":"9","author":"Ploug","year":"2003","journal-title":"Curr. Pharm. Des."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1006\/bcmd.1996.0111","article-title":"Structure-function relationships of the complement regulatory protein, CD59","volume":"22","author":"Petranka","year":"1996","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"12166","DOI":"10.1021\/bi981227y","article-title":"Differential roles for disulfide bonds in the structural integrity and biological activity of kappa-Bungarotoxin, a neuronal nicotinic acetylcholine receptor antagonist","volume":"37","author":"Grant","year":"1998","journal-title":"Biochemistry"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1182\/blood-2010-03-276642","article-title":"Selective abrogation of the uPA-uPAR interaction in vivo reveals a novel role in suppression of fibrin-associated inflammation","volume":"116","author":"Connolly","year":"2010","journal-title":"Blood"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"10310","DOI":"10.1523\/JNEUROSCI.1630-17.2017","article-title":"A Cross Talk between Neuronal Urokinase-type Plasminogen Activator (uPA) and Astrocytic uPA Receptor (uPAR) Promotes Astrocytic Activation and Synaptic Recovery in the Ischemic Brain","volume":"37","author":"Diaz","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2741","DOI":"10.1074\/jbc.M116.761650","article-title":"Urokinase-type Plasminogen Activator (uPA) Binding to the uPA Receptor (uPAR) Promotes Axonal Regeneration in the Central Nervous System","volume":"292","author":"Merino","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"957","DOI":"10.4049\/jimmunol.1701317","article-title":"Antibody-Mediated Neutralization of uPA Proteolytic Function Reduces Disease Progression in Mouse Arthritis Models","volume":"200","author":"Almholt","year":"2018","journal-title":"J. Immunol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1182\/bloodadvances.2016004002","article-title":"Urokinase plasminogen activator and receptor promote collagen-induced arthritis through expression in hematopoietic cells","volume":"1","author":"Thornton","year":"2017","journal-title":"Blood Adv."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.2174\/138945011797635902","article-title":"uPAR as anti-cancer target: Evaluation of biomarker potential, histological localization, and antibody-based therapy","volume":"12","author":"Lund","year":"2011","journal-title":"Curr. Drug Targets"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.2174\/138945011797635812","article-title":"Rational Targeting of the Urokinase Receptor (uPAR): Development of Antagonists and Non-Invasive Imaging Probes","volume":"12","author":"Kriegbaum","year":"2011","journal-title":"Curr. Drug Targets"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1016\/j.nucmedbio.2012.05.007","article-title":"New peptide receptor radionuclide therapy of invasive cancer cells: In vivo studies using 177Lu-DOTA-AE105 targeting uPAR in human colorectal cancer xenografts","volume":"39","author":"Persson","year":"2012","journal-title":"Nucl. Med. Biol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1002\/cmdc.201700572","article-title":"Mimicking Intermolecular Interactions of Tight Protein-Protein Complexes for Small-Molecule Antagonists","volume":"12","author":"Xu","year":"2017","journal-title":"ChemMedChem"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"12157","DOI":"10.1021\/bi010662g","article-title":"Peptide-derived antagonists of the urokinase receptor. affinity maturation by combinatorial chemistry, identification of functional epitopes, and inhibitory effect on cancer cell intravasation","volume":"40","author":"Ploug","year":"2001","journal-title":"Biochemistry"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"618","DOI":"10.7150\/thno.6810","article-title":"Improved PET imaging of uPAR expression using new (64)Cu-labeled cross-bridged peptide ligands: Comparative in vitro and in vivo studies","volume":"3","author":"Persson","year":"2013","journal-title":"Theranostics"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.7150\/thno.12956","article-title":"First-in-human uPAR PET: Imaging of Cancer Aggressiveness","volume":"5","author":"Persson","year":"2015","journal-title":"Theranostics"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"467","DOI":"10.7150\/thno.3791","article-title":"Structure-driven design of radionuclide tracers for non-invasive imaging of uPAR and targeted radiotherapy. The tale of a synthetic peptide antagonist","volume":"3","author":"Ploug","year":"2013","journal-title":"Theranostics"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.oraloncology.2016.12.026","article-title":"Preclinical uPAR-targeted multimodal imaging of locoregional oral cancer","volume":"66","author":"Boonstra","year":"2017","journal-title":"Oral Oncol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"3833","DOI":"10.1021\/acs.bioconjchem.8b00669","article-title":"Molecular Targeted NIR-II Probe for Image-Guided Brain Tumor Surgery","volume":"29","author":"Kurbegovic","year":"2018","journal-title":"Bioconjugate Chem."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1038\/nsmb.1404","article-title":"Crystal structures of two human vitronectin, urokinase and urokinase receptor complexes","volume":"15","author":"Huai","year":"2008","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"33544","DOI":"10.1074\/jbc.M111.220087","article-title":"Conformational regulation of urokinase receptor function: Impact of receptor occupancy and epitope-mapped monoclonal antibodies on lamellipodia induction","volume":"286","author":"Gardsvoll","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"43515","DOI":"10.1074\/jbc.M111.300020","article-title":"Mimicry of the regulatory role of urokinase in lamellipodia formation by introduction of a non-native interdomain disulfide bond in its receptor","volume":"286","author":"Gardsvoll","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.jmb.2011.12.058","article-title":"Crystal structure of the urokinase receptor in a ligand-free form","volume":"416","author":"Xu","year":"2012","journal-title":"J. Mol. Biol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1016\/j.jmb.2015.01.022","article-title":"Stabilizing a flexible interdomain hinge region harboring the SMB binding site drives uPAR into its closed conformation","volume":"427","author":"Zhao","year":"2015","journal-title":"J. Mol. Biol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"34304","DOI":"10.1074\/jbc.M112.398404","article-title":"A flexible multidomain structure drives the function of the urokinase-type plasminogen activator receptor (uPAR)","volume":"287","author":"Mertens","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"7403","DOI":"10.1074\/jbc.RA119.007847","article-title":"Did evolution create a flexible ligand-binding cavity in the urokinase receptor through deletion of a plesiotypic disulfide bond?","volume":"294","author":"Leth","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Chana-Mu\u00f1oz, A., Jendroszek, A., S\u00f8nnichsen, M., Wang, T., Ploug, M., Jensen, J.K., Andreasen, P.A., Bendixen, C., and Panitz, F. (2019). Origin and diversification of the plasminogen activation system among chordates. BMC Evol. Biol., 19.","DOI":"10.1186\/s12862-019-1353-z"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1042\/bj20031478","article-title":"Structural analysis and tissue localization of human C4.4A: A protein homologue of the urokinase receptor","volume":"380","author":"Hansen","year":"2004","journal-title":"Biochem. J."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1369\/0022155414563107","article-title":"Expression of the Ly6\/uPAR-domain proteins C4.4A and Haldisin in non-invasive and invasive skin lesions","volume":"63","author":"Kriegbaum","year":"2015","journal-title":"J. Histochem. Cytochem."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1369\/0022155410394859","article-title":"Expression of C4.4A, a structural uPAR homolog, reflects squamous epithelial differentiation in the adult mouse and during embryogenesis","volume":"59","author":"Kriegbaum","year":"2011","journal-title":"J. Histochem. Cytochem."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1369\/0022155413501879","article-title":"The Urokinase Receptor Homolog Haldisin Is a Novel Differentiation Marker of Stratum Granulosum in Squamous Epithelia","volume":"61","author":"Kriegbaum","year":"2013","journal-title":"J. Histochem. Cytochem."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"25833","DOI":"10.1038\/srep25833","article-title":"C4.4A gene ablation is compatible with normal epidermal development and causes modest overt phenotypes","volume":"6","author":"Kriegbaum","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.lungcan.2007.06.025","article-title":"Tumour cell expression of C4.4A, a structural homologue of the urokinase receptor, correlates with poor prognosis in non-small cell lung cancer","volume":"58","author":"Hansen","year":"2007","journal-title":"Lung Cancer"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1097\/JTO.0b013e318279d503","article-title":"Ly6\/uPAR-related protein C4.4A as a marker of solid growth pattern and poor prognosis in lung adenocarcinoma","volume":"8","author":"Jacobsen","year":"2013","journal-title":"J. Thorac. Oncol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"2734","DOI":"10.1002\/ijc.26305","article-title":"Expression of C4.4A in precursor lesions of pulmonary adenocarcinoma and squamous cell carcinoma","volume":"130","author":"Jacobsen","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"a022103","DOI":"10.1101\/cshperspect.a022103","article-title":"Structural Biology and Evolution of the TGF-beta Family","volume":"8","author":"Hinck","year":"2016","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nsmb756","article-title":"Molecular recognition of BMP-2 and BMP receptor IA","volume":"11","author":"Keller","year":"2004","journal-title":"Nat. Struct. Mol. Biol"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.bbrc.2006.10.109","article-title":"High resolution structures of the bone morphogenetic protein type II receptor in two crystal forms: Implications for ligand binding","volume":"351","author":"Mace","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"3152","DOI":"10.1002\/1873-3468.13212","article-title":"Structure of the Wnt signaling enhancer LYPD6 and its interactions with the Wnt coreceptor LRP6","volume":"592","author":"Zhao","year":"2018","journal-title":"FEBS Lett."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/11\/2760\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:56:18Z","timestamp":1760187378000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/11\/2760"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,5]]},"references-count":120,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2019,6]]}},"alternative-id":["ijms20112760"],"URL":"https:\/\/doi.org\/10.3390\/ijms20112760","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,5]]}}}