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Licensed Unlicensed Requires Authentication Published by De Gruyter August 3, 2021

The extracellular region of bovine milk butyrophilin exhibits closer structural similarity to human myelin oligodendrocyte glycoprotein than to immunological BTN family receptors

  • Andreas Eichinger ORCID logo , Irmgard Neumaier and Arne Skerra ORCID logo EMAIL logo
From the journal Biological Chemistry


Bovine butyrophilin (BTN1A1) is an abundant type I transmembrane glycoprotein exposed on the surface of milk fat globules. We have solved the crystal structure of its extracellular region via multiple wavelength anomalous dispersion after incorporation of selenomethionine into the bacterially produced protein. The butyrophilin ectodomain exhibits two subdomains with immunoglobulin fold, each comprising a β-sandwich with a central disulfide bridge as well as one N-linked glycosylation. The fifth Cys residue at position 193 is unpaired and prone to forming disulfide crosslinks. The apparent lack of a ligand-binding site or receptor activity suggests a function predominantly as hydrophilic coat protein to prevent coagulation of the milk fat droplets. While there is less structural resemblance to members of the human butyrophilin family such as BTN3A, which play a role as immune receptors, the N-terminal bovine butyrophilin subdomain shows surprising similarity to the human myelin oligodendrocyte glycoprotein, a protein exposed on the surface of myelin sheaths. Thus, our study lends structural support to earlier hypotheses of a correlation between the consumption of cow milk and prevalence of neurological autoimmune diseases and may offer guidance for the breeding of cattle strains that express modified butyrophilin showing less immunological cross-reactivity.

Corresponding author: Arne Skerra, Lehrstuhl für Biologische Chemie, Technische Universität München, Emil-Erlenmeyer-Forum 5, D-85354 Freising, Germany, E-mail:

Funding source: Helmholtz-Zentrum Berlin für Materialien und Energie


The authors wish to thank Dr. Carolin Farke and Prof. Heinrich H.D. Meyer (TUM Lehrstuhl für Physiologie) for the donation of cDNA, Walter Stelzer (TUM Lehrstuhl für Chemie der Biopolymere) for MS analysis, Ina Theobald (TUM Lehrstuhl für Biologische Chemie) for experimental assistance and Dr. Manfred S. Weiss (Helmholtz-Zentrum Berlin, Germany) for technical support at BESSY beamline 14.1.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: This work was financially supported by the Helmholtz-Zentrum Berlin.

  3. Conflict of interest statement: The authors declare no conflicts of interest regarding this article.


Abeler-Dörner, L., Swamy, M., Williams, G., Hayday, A.C., and Bas, A. (2012). Butyrophilins: an emerging family of immune regulators. Trends Immunol. 33: 34–41, in Google Scholar

Afrache, H., Gouret, P., Ainouche, S., Pontarotti, P., and Olive, D. (2012). The butyrophilin (BTN) gene family: from milk fat to the regulation of the immune response. Immunogenetics 64: 781–794, in Google Scholar

Altschul, S.F., Gish, W., Miller, W., Myers, E.W., and Lipman, D.J. (1990). Basic local alignment search tool. J. Mol. Biol. 215: 403–410, in Google Scholar

Arnett, H.A. and Viney, J.L. (2014). Immune modulation by butyrophilins. Nat. Rev. Immunol. 14: 559–569, in Google Scholar

Beltrán, E., Paunovic, M., Gebert, D., Cesur, E., Jeitler, M., Höftberger, R., Malotka, J., Mader, S., Kawakami, N., Meinl, E., Bradl, M., Dornmair, K., and Lassmann, H. (2021). Archeological neuroimmunology: resurrection of a pathogenic immune response from a historical case sheds light on human autoimmune encephalomyelitis and multiple sclerosis. Acta Neuropathol. 141: 67–83.10.1007/s00401-020-02239-2Search in Google Scholar

Bhattacharya, T.K., Misra, S.S., Sheikh, F.D., Dayal, S., Vohra, V., Kumar, P., and Sharma, A. (2004). Variability of milk fat globule membrane protein gene between cattle and riverine buffalo. DNA Seq. 15: 326–331, in Google Scholar

Bleasby, A.J., Akrigg, D., and Attwood, T.K. (1994). OWL – a non-redundant composite protein sequence database. Nucleic Acids Res. 22: 3574–3577.Search in Google Scholar

Bohne, A., Lang, E., and von der Lieth, C.W. (1999). SWEET – WWW-based rapid 3D construction of oligo- and polysaccharides. Bioinformatics 15: 767–768, in Google Scholar

Bohne-Lang, A., and von der Lieth, C.W. (2005). GlyProt: in silico glycosylation of proteins. Nucleic Acids Res. 33: W214–W219, in Google Scholar

Bond, C.S., and Schüttelkopf, A.W. (2009). ALINE: a WYSIWYG protein-sequence alignment editor for publication-quality alignments. Acta Crystallogr. D Biol. Crystallogr. 65: 510–512, in Google Scholar

Bork, P., Holm, L., and Sander, C. (1994). The immunoglobulin fold. Structural classification, sequence patterns and common core. J. Mol. Biol. 242: 309–320, in Google Scholar

Breithaupt, C., Schäfer, B., Pellkofer, H., Huber, R., Linington, C., and Jacob, U. (2008). Demyelinating myelin oligodendrocyte glycoprotein-specific autoantibody response is focused on one dominant conformational epitope region in rodents. J. Immunol. 181: 1255–1263, in Google Scholar

Breithaupt, C., Schubart, A., Zander, H., Skerra, A., Huber, R., Linington, C., and Jacob, U. (2003). Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein. Proc. Natl. Acad. Sci. U. S. A. 100: 9446–9451, doi: in Google Scholar

Breustedt, D.A., Korndörfer, I.P., Redl, B., and Skerra, A. (2005). The 1.8-Å crystal structure of human tear lipocalin reveals an extended branched cavity with capacity for multiple ligands. J. Biol. Chem. 280: 484–493, in Google Scholar

Breza, M., Koutsis, G., Tzartos, J.S., Velonakis, G., Evangelopoulos, M.E., Tzanetakos, D., Karagiorgou, K., Angelopoulou, G., Kasselimis, D., Potagas, C., Anagnostouli, M., Stefanis, L., and Kilidireas, C. (2019). MOG antibody-associated demyelinating disease mimicking typical multiple sclerosis: a case for expanding anti-MOG testing? Mult. Scler. Relat. Disord. 33: 67–69, in Google Scholar

Brilot, F., Dale, R.C., Selter, R.C., Grummel, V., Kalluri, S.R., Aslam, M., Busch, V., Zhou, D., Cepok, S., and Hemmer, B. (2009). Antibodies to native myelin oligodendrocyte glycoprotein in children with inflammatory demyelinating central nervous system disease. Ann. Neurol. 66: 833–842, in Google Scholar

Brunner, C., Lassmann, H., Waehneldt, T.V., Matthieu, J.M., and Linington, C. (1989). Differential ultrastructural localization of myelin basic protein, myelin/oligodendroglial glycoprotein, and 2′,3′-cyclic nucleotide 3′-phosphodiesterase in the CNS of adult rats. J. Neurochem. 52: 296–304, in Google Scholar

Bullock, W.O., Fernandez, J.M., and Short, J.M. (1987). XL1-Blue: a high efficiency plasmid transforming recA Escherichia coli strain with β-galactosidase selection. Biotechniques 5: 376–379.Search in Google Scholar

CCP4. (1994). The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D 50: 760–763.10.1107/S0907444994003112Search in Google Scholar PubMed

Challa, D.K., Bussmeyer, U., Khan, T., Montoyo, H.P., Bansal, P., Ober, R.J., and Ward, E.S. (2013). Autoantibody depletion ameliorates disease in murine experimental autoimmune encephalomyelitis. mAbs 5: 655–659, in Google Scholar

Clements, C.S., Reid, H.H., Beddoe, T., Tynan, F.E., Perugini, M.A., Johns, T.G., Bernard, C.C., and Rossjohn, J. (2003). The crystal structure of myelin oligodendrocyte glycoprotein, a key autoantigen in multiple sclerosis. Proc. Natl. Acad. Sci. U. S. A. 100: 11059–11064, doi: in Google Scholar

Cobo-Calvo, A., Vukusic, S., and Marignier, R. (2019). Clinical spectrum of central nervous system myelin oligodendrocyte glycoprotein autoimmunity in adults. Curr. Opin. Neurol. 32: 459–466, in Google Scholar

Colombo, G., Reggiani, F., Podesta, M.A., Garavaglia, M.L., Portinaro, N.M., Milzani, A., Badalamenti, S., and Dalle-Donne, I. (2015). Plasma protein thiolation index (PTI) as a biomarker of thiol-specific oxidative stress in haemodialyzed patients. Free Radic. Biol. Med. 89: 443–451, in Google Scholar

Compte, E., Pontarotti, P., Collette, Y., Lopez, M., and Olive, D. (2004). Frontline: characterization of BT3 molecules belonging to the B7 family expressed on immune cells. Eur. J. Immunol. 34: 2089–2099, in Google Scholar

Daetwyler, H.D., Capitan, A., Pausch, H., Stothard, P., van Binsbergen, R., Brondum, R.F., Liao, X., Djari, A., Rodriguez, S.C., Grohs, C., et al.. (2014). Whole-genome sequencing of 234 bulls facilitates mapping of monogenic and complex traits in cattle. Nat. Genet. 46: 858–865, in Google Scholar

Davey, H.W., Ogg, S.L., Husaini, Y., Snell, R.G., Korobko, I.V., Mather, I.H., and Wilkins, R.J. (1997). Structure and sequence of the bovine butyrophilin gene. Gene 199: 57–62, in Google Scholar

DeLano, W.L. (2002). The PyMOL molecular graphics system. San Carlos, CA, USA: DeLano Scientific.Search in Google Scholar

Dewettinck, K., Rombaut, R., Thienpont, N., Le, T.T., Messens, K., and Van Camp, J. (2008). Nutritional and technological aspects of milk fat globule membrane material. Int. Dairy J. 18: 436–457, in Google Scholar

Eichinger, A., Nasreen, A., Kim, H.J., and Skerra, A. (2007). Structural insight into the dual ligand specificity and mode of high density lipoprotein association of apolipoprotein D. J. Biol. Chem. 282: 31068–31075, in Google Scholar

Emsley, P., Lohkamp, B., Scott, W.G., and Cowtan, K. (2010). Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66: 486–501, in Google Scholar

Fling, S.P. and Gregerson, D.S. (1986). Peptide and protein molecular weight determination by electrophoresis using a high-molarity tris buffer system without urea. Anal. Biochem. 155: 83–88, in Google Scholar

Gasteiger, E., Gattiker, A., Hoogland, C., Ivanyi, I., Appel, R.D., and Bairoch, A. (2003). ExPASy: the proteomics server for in-depth protein knowledge and analysis. Nucleic Acids Res. 31: 3784–3788.10.1093/nar/gkg563Search in Google Scholar PubMed PubMed Central

Guggenmos, J., Schubart, A.S., Ogg, S., Andersson, M., Olsson, T., Mather, I.H., and Linington, C. (2004). Antibody cross-reactivity between myelin oligodendrocyte glycoprotein and the milk protein butyrophilin in multiple sclerosis. J. Immunol. 172: 661–668, in Google Scholar

Hendrickson, W.A. and Ogata, C.M. (1997). Phase determination from multiwavelength anomalous diffraction measurements. Methods Enzymol. 276: 494–523, in Google Scholar

Holm, L., Kaariainen, S., Rosenstrom, P., and Schenkel, A. (2008). Searching protein structure databases with DaliLite v.3. Bioinformatics 24: 2780–2781, in Google Scholar

Hooft, R.W., Vriend, G., Sander, C., and Abola, E.E. (1996). Errors in protein structures. Nature 381: 272, in Google Scholar

Husaini, Y., Wilkins, R.J., and Davey, H.W. (1999). Identification of five point mutations, including an AluI RFLP, in the bovine butyrophilin gene. Anim. Genet. 30: 400–401, in Google Scholar

Irwin, J.J., Shoichet, B.K., Mysinger, M.M., Huang, N., Colizzi, F., Wassam, P., and Cao, Y. (2009). Automated docking screens: a feasibility study. J. Med. Chem. 52: 5712–5720, in Google Scholar

Irwin, J.J., Sterling, T., Mysinger, M.M., Bolstad, E.S., and Coleman, R.G. (2012). ZINC: a free tool to discover chemistry for biology. J. Chem. Inf. Model. 52: 1757–1768, in Google Scholar

Jabed, A., Wagner, S., McCracken, J., Wells, D.N., and Laible, G. (2012). Targeted microRNA expression in dairy cattle directs production of β-lactoglobulin-free, high-casein milk. Proc. Natl. Acad. Sci. U. S. A. 109: 16811–16816 (correction in vol. 00113, no. 00051, E18354–E18356), in Google Scholar

Jack, L.J. and Mather, I.H. (1990). Cloning and analysis of cDNA encoding bovine butyrophilin, an apical glycoprotein expressed in mammary tissue and secreted in association with the milk-fat globule membrane during lactation. J. Biol. Chem. 265: 14481–14486, in Google Scholar

Jeong, J., Lisinski, I., Kadegowda, A.K., Shin, H., Wooding, F.B., Daniels, B.R., Schaack, J., and Mather, I.H. (2013). A test of current models for the mechanism of milk-lipid droplet secretion. Traffic 14: 974–986, in Google Scholar

Johns, T.G. and Bernard, C.C. (1999). The structure and function of myelin oligodendrocyte glycoprotein. J. Neurochem. 72: 1–9, in Google Scholar

Kabsch, W. and Sander, C. (1983). Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 22: 2577–2637, in Google Scholar

Krienke, C., Kolb, L., Diken, E., Streuber, M., Kirchhoff, S., Bukur, T., Akilli-Öztürk, Ö., Kranz, L.M., Berger, H., Petschenka, J., et al.. (2021). A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis. Science 371: 145–153, in Google Scholar

Krissinel, E. and Henrick, K. (2007). Inference of macromolecular assemblies from crystalline state. J. Mol. Biol. 372: 774–797, in Google Scholar

Lalive, P.H., Molnarfi, N., Benkhoucha, M., Weber, M.S., and Santiago-Raber, M.L. (2011). Antibody response in MOG35–55 induced EAE. J. Neuroimmunol. 240–241: 28–33, in Google Scholar

Larkin, M.A., Blackshields, G., Brown, N.P., Chenna, R., McGettigan, P.A., McWilliam, H., Valentin, F., Wallace, I.M., Wilm, A., Lopez, R., et al.. (2007). Clustal W and clustal X version 2.0. Bioinformatics 23: 2947–2948, in Google Scholar

Laskowski, R.A., MacArthur, M.W., Mos, D.S., and Thornton, J.M. (1993). PROCHECK: a program to check the stereochemical quality of protein structures. J. Appl. Crystallogr. 26: 283–291, in Google Scholar

Lebar, R., Baudrimont, M., and Vincent, C. (1989). Chronic experimental autoimmune encephalomyelitis in the Guinea pig. Presence of anti-M2 antibodies in central nervous system tissue and the possible role of M2 autoantigen in the induction of the disease. J. Autoimmun. 2: 115–132, in Google Scholar

Lin, D.Y., Tanaka, Y., Iwasaki, M., Gittis, A.G., Su, H.P., Mikami, B., Okazaki, T., Honjo, T., Minato, N., and Garboczi, D.N. (2008). The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors. Proc. Natl. Acad. Sci. U. S. A. 105: 3011–3016, in Google Scholar

Linnington, C., Webb, M., and Woodhams, P.L. (1984). A novel myelin-associated glycoprotein defined by a mouse monoclonal antibody. J. Neuroimmunol. 6: 387–396, in Google Scholar

Loers, G., Cui, Y.F., Neumaier, I., Schachner, M., and Skerra, A. (2014). A Fab fragment directed against the neural cell adhesion molecule L1 enhances functional recovery after injury of the adult mouse spinal cord. Biochem. J. 460: 437–446, in Google Scholar

Malosse, D. and Perron, H. (1993). Correlation analysis between bovine populations, other farm animals, house pets, and multiple sclerosis prevalence. Neuroepidemiology 12: 15–27, in Google Scholar

Malosse, D., Perron, H., Sasco, A., and Seigneurin, J.M. (1992). Correlation between milk and dairy product consumption and multiple sclerosis prevalence: a worldwide study. Neuroepidemiology 11: 304–312, in Google Scholar

Mañá, P., Goodyear, M., Bernard, C., Tomioka, R., Freire-Garabal, M., and Liñares, D. (2004). Tolerance induction by molecular mimicry: prevention and suppression of experimental autoimmune encephalomyelitis with the milk protein butyrophilin. Int. Immunol. 16: 489–499, in Google Scholar

Mather, I.H. and Keenan, T.W. (1998). Origin and secretion of milk lipids. J. Mammary Gland Biol. Neoplasia 3: 259–273, in Google Scholar

Mather, I.H. (2000). A review and proposed nomenclature for major proteins of the milk-fat globule membrane. J. Dairy Sci. 83: 203–247, in Google Scholar

Menge, T., Lalive, P.H., von Büdingen, H.C., and Genain, C.P. (2011). Conformational epitopes of myelin oligodendrocyte glycoprotein are targets of potentially pathogenic antibody responses in multiple sclerosis. J. Neuroinflammation 8: 161.10.1186/1742-2094-8-161Search in Google Scholar PubMed PubMed Central

Mueller, U., Darowski, N., Fuchs, M.R., Forster, R., Hellmig, M., Paithankar, K.S., Puhringer, S., Steffien, M., Zocher, G., and Weiss, M.S. (2012). Facilities for macromolecular crystallography at the Helmholtz-Zentrum Berlin. J. Synchrotron Radiat. 19: 442–449, in Google Scholar

Narayan, R., Simpson, A., Fritsche, K., Salama, S., Pardo, S., Mealy, M., Paul, F., and Levy, M. (2018). MOG antibody disease: a review of MOG antibody seropositive neuromyelitis optica spectrum disorder. Mult. Scler. Relat. Disord. 25: 66–72, in Google Scholar

Ogg, S.L., Weldon, A.K., Dobbie, L., Smith, A.J., and Mather, I.H. (2004). Expression of butyrophilin (Btn1a1) in lactating mammary gland is essential for the regulated secretion of milk-lipid droplets. Proc. Natl. Acad. Sci. U. S. A. 101: 10084–10089, in Google Scholar

Palakodeti, A., Sandstrom, A., Sundaresan, L., Harly, C., Nedellec, S., Olive, D., Scotet, E., Bonneville, M., and Adams, E.J. (2012). The molecular basis for modulation of human Vγ9Vδ2 T cell responses by CD277/butyrophilin-3 (BTN3A)-specific antibodies. J. Biol. Chem. 287: 32780–32790, in Google Scholar

Panjikar, S., Parthasarathy, V., Lamzin, V.S., Weiss, M.S., and Tucker, P.A. (2005). Auto-Rickshaw: an automated crystal structure determination platform as an efficient tool for the validation of an X-ray diffraction experiment. Acta Crystallogr. D Biol. Crystallogr. 61: 449–457, in Google Scholar

Payne, K.K., Mine, J.A., Biswas, S., Chaurio, R.A., Perales-Puchalt, A., Anadon, C.M., Costich, T.L., Harro, C.M., Walrath, J., Ming, Q., et al.. (2020). BTN3A1 governs antitumor responses by coordinating αβ and γδ T cells. Science 369: 942–949, in Google Scholar

Peterson, J.A., Scallan, C.D., Ceriani, R.L., and Hamosh, M. (2001). Structural and functional aspects of three major glycoproteins of the human milk fat globule membrane. Adv. Exp. Med. Biol. 501: 179–187, in Google Scholar

Reindl, M. and Waters, P. (2019). Myelin oligodendrocyte glycoprotein antibodies in neurological disease. Nat. Rev. Neurol. 15: 89–102, in Google Scholar

Rhodes, D.A., Stammers, M., Malcherek, G., Beck, S., and Trowsdale, J. (2001). The cluster of BTN genes in the extended major histocompatibility complex. Genomics 71: 351–362, in Google Scholar

Rhodes, D.A., de Bono, B., and Trowsdale, J. (2005). Relationship between SPRY and B30.2 protein domains. Evolution of a component of immune defence? Immunology 116: 411–417, in Google Scholar

Rhodes, D.A., Reith, W., and Trowsdale, J. (2016). Regulation of immunity by butyrophilins. Annu. Rev. Immunol. 34: 151–172, in Google Scholar

Rigau, M., Ostrouska, S., Fulford, T.S., Johnson, D.N., Woods, K., Ruan, Z., McWilliam, H.E.G., Hudson, C., Tutuka, C., Wheatley, A.K., et al.. (2020). Butyrophilin 2A1 is essential for phosphoantigen reactivity by γδ T cells. Science 367: eaay5516, doi: in Google Scholar

Robenek, H., Hofnagel, O., Buers, I., Lorkowski, S., Schnoor, M., Robenek, M.J., Heid, H., Troyer, D., and Severs, N.J. (2006). Butyrophilin controls milk fat globule secretion. Proc. Natl. Acad. Sci. U. S. A. 103: 10385–10390, doi: in Google Scholar

Rutter, E.R.F. (2006). Multiple sclerosis and milk: to drink or not to drink? Int. J. Dairy Technol. 59: 223–228, in Google Scholar

Sambrook, J., Fritsch, E.F., and Maniatis, T. (1989). Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.Search in Google Scholar

Sato, T., Takio, K., Kobata, A., Greenwalt, D.E., and Furukawa, K. (1995). Site-specific glycosylation of bovine butyrophilin. J. Biochem. 117: 147–157, in Google Scholar

Sawyer, L. and Kontopidis, G. (2000). The core lipocalin, bovine β-lactoglobulin. Biochim. Biophys. Acta 1482: 136–148, in Google Scholar

Schlapschy, M., Grimm, S., and Skerra, A. (2006). A system for concomitant overexpression of four periplasmic folding catalysts to improve secretory protein production in Escherichia coli. Protein Eng. Des. Sel. 19: 385–390, in Google Scholar

Schluesener, H.J., Sobel, R.A., Linington, C., and Weiner, H.L. (1987). A monoclonal antibody against a myelin oligodendrocyte glycoprotein induces relapses and demyelination in central nervous system autoimmune disease. J. Immunol. 139: 4016–4021.10.4049/jimmunol.139.12.4016Search in Google Scholar

Schmidt, T.G.M., Eichinger, A., Schneider, M., Bonet, L., Carl, U., Karthaus, D., Theobald, I., and Skerra, A. (2021). The role of changing loop conformations in streptavidin versions engineered for high-affinity binding of the Strep-tag II peptide. J. Mol. Biol. 433: 166893, doi: in Google Scholar

Schmidt, T.G. and Skerra, A. (2007). The Strep-tag system for one-step purification and high-affinity detection or capturing of proteins. Nat. Protoc. 2: 1528–1535, doi: in Google Scholar

Shamimuzzaman, M., Le Tourneau, J.J., Unni, D.R., Diesh, C.M., Triant, D.A., Walsh, A.T., Tayal, A., Conant, G.C., Hagen, D.E., and Elsik, C.G. (2020). Bovine Genome Database: new annotation tools for a new reference genome. Nucleic Acids Res. 48: D676–D681, in Google Scholar

Skerra, A. (1993). Bacterial expression of immunoglobulin fragments. Curr. Opin. Immunol. 5: 256–262, in Google Scholar

Skerra, A. (1994a). Use of the tetracycline promoter for the tightly regulated production of a murine antibody fragment in Escherichia coli. Gene 151: 131–135, in Google Scholar

Skerra, A. (1994b). A general vector, pASK84, for cloning, bacterial production, and single-step purification of antibody Fab fragments. Gene 141: 79–84, in Google Scholar

Spadaro, M., Gerdes, L.A., Krumbholz, M., Ertl-Wagner, B., Thaler, F.S., Schuh, E., Metz, I., Blaschek, A., Dick, A., Bruck, W., et al.. (2016). Autoantibodies to MOG in a distinct subgroup of adult multiple sclerosis. Neurol. Neuroimmunol. Neuroinflamm. 3: e257, in Google Scholar

Spertino, S., Cipriani, V., De Angelis, C., Giuffrida, M.G., Marsano, F., and Cavaletto, M. (2012). Proteome profile and biological activity of caprine, bovine and human milk fat globules. Mol. Biosyst. 8: 967–974, in Google Scholar

Stefferl, A., Schubart, A., Storch, M., Amini, A., Mather, I., Lassmann, H., and Linington, C. (2000). Butyrophilin, a milk protein, modulates the encephalitogenic T cell response to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis. J. Immunol. 165: 2859–2865, in Google Scholar

Taylor, M.R., Peterson, J.A., Ceriani, R.L., and Couto, J.R. (1996). Cloning and sequence analysis of human butyrophilin reveals a potential receptor function. Biochim. Biophys. Acta 1306: 1–4, in Google Scholar

Tazi-Ahnini, R., Henry, J., Offer, C., Bouissou-Bouchouata, C., Mather, I.H., and Pontarotti, P. (1997). Cloning, localization, and structure of new members of the butyrophilin gene family in the juxta-telomeric region of the major histocompatibility complex. Immunogenetics 47: 55–63, in Google Scholar

Uhlén, M., Bjorling, E., Agaton, C., Szigyarto, C.A., Amini, B., Andersen, E., Andersson, A.C., Angelidou, P., Asplund, A., Asplund, C., et al.. (2005). A human protein atlas for normal and cancer tissues based on antibody proteomics. Mol. Cell. Proteomics 4: 1920–1932, in Google Scholar

Vavassori, S., Kumar, A., Wan, G.S., Ramanjaneyulu, G.S., Cavallari, M., El Daker, S., Beddoe, T., Theodossis, A., Williams, N.K., Gostick, E., et al.. (2013). Butyrophilin 3A1 binds phosphorylated antigens and stimulates human γδ T cells. Nat. Immunol. 14: 908–916, in Google Scholar

Vojdani, A., Kharrazian, D., and Mukherjee, P.S. (2013). The prevalence of antibodies against wheat and milk proteins in blood donors and their contribution to neuroimmune reactivities. Nutrients 6: 15–36, in Google Scholar

Voss, S. and Skerra, A. (1997). Mutagenesis of a flexible loop in streptavidin leads to higher affinity for the Strep-tag II peptide and improved performance in recombinant protein purification. Protein Eng. 10: 975–982, doi: in Google Scholar

Wang, J., Manick, B., Wu, G., and Kalabokis, V. (2016). Immune modulation by butyrophilin 1A1 (BTN1A1). J. Immunol. 196(Suppl. 199): 191.10.4049/jimmunol.196.Supp.199.1Search in Google Scholar

Weber, M.S., Derfuss, T., Metz, I., and Bruck, W. (2018). Defining distinct features of anti-MOG antibody associated central nervous system demyelination. Ther. Adv. Neurol. Disord. 11: 1756286418762083.10.1177/1756286418762083Search in Google Scholar PubMed PubMed Central

Weichenberger, C.X. and Sippl, M.J. (2007). NQ-Flipper: recognition and correction of erroneous asparagine and glutamine side-chain rotamers in protein structures. Nucleic Acids Res. 35: W403–W406, in Google Scholar

Willcox, C.R., Mohammed, F., and Willcox, B.E. (2013). Resolving the mystery of pyrophosphate antigen presentation. Nat. Immunol. 14: 886–887, in Google Scholar

Winer, S., Astsaturov, I., Cheung, R.K., Schrade, K., Gunaratnam, L., Wood, D.D., Moscarello, M.A., O’Connor, P., McKerlie, C., Becker, D.J., et al.. (2001). T cells of multiple sclerosis patients target a common environmental peptide that causes encephalitis in mice. J. Immunol. 166: 4751–4756, in Google Scholar

Winn, M.D., Ballard, C.C., Cowtan, K.D., Dodson, E.J., Emsley, P., Evans, P.R., Keegan, R.M., Krissinel, E.B., Leslie, A.G., McCoy, A., et al.. (2011). Overview of the CCP4 suite and current developments. Acta Crystallogr. D Biol. Crystallogr. 67: 235–242, in Google Scholar

Woo, J.S., Imm, J.H., Min, C.K., Kim, K.J., Cha, S.S., and Oh, B.H. (2006). Structural and functional insights into the B30.2/SPRY domain. EMBO J. 25: 1353–1363, in Google Scholar

Wright, A.V., Nunez, J.K., and Doudna, J.A. (2016). Biology and applications of CRISPR systems: harnessing nature’s toolbox for genome engineering. Cell 164: 29–44, in Google Scholar

Yamashiro, H., Yoshizaki, S., Tadaki, T., Egawa, K., and Seo, N. (2010). Stimulation of human butyrophilin 3 molecules results in negative regulation of cellular immunity. J. Leukoc. Biol. 88: 757–767, in Google Scholar

Yanisch-Perron, C., Vieira, J., and Messing, J. (1985). Improved M13 phage cloning vectors and host strains: nucleotide sequences of the M13mp18 and pUC19 vectors. Gene 33: 103–119, in Google Scholar

Ye, Y. and Godzik, A. (2004). FATCAT: a web server for flexible structure comparison and structure similarity searching. Nucleic Acids Res. 32: W582–W585, in Google Scholar

Zhang, X., Schwartz, J.C., Almo, S.C., and Nathenson, S.G. (2003). Crystal structure of the receptor-binding domain of human B7-2: insights into organization and signaling. Proc. Natl. Acad. Sci. U. S. A. 100: 2586–2591, in Google Scholar

Zuniga, R.N., Tolkach, A., Kulozik, U., and Aguilera, J.M. (2010). Kinetics of formation and physicochemical characterization of thermally-induced β-lactoglobulin aggregates. J. Food Sci. 75: E261–E268, in Google Scholar

Supplementary Material

The online version of this article offers supplementary material (

Received: 2021-01-24
Accepted: 2021-06-17
Published Online: 2021-08-03
Published in Print: 2021-09-27

© 2021 Walter de Gruyter GmbH, Berlin/Boston

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