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β-Lactoglobulin

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β-Lactoglobulin
Ribbon structure of a β-lactoglobulin subunit (PDB: 3BLG​). Rendered with Kinemage.
Identifiers
OrganismBos taurus
SymbolBLG
UniProtP02754
Search for
StructuresSwiss-model
DomainsInterPro

β-Lactoglobulin (beta-lactoglobulin, BLG, Bos d 5) is the major whey protein of cow and sheep's milk (~3 g/L), and is also present in many other mammalian species; a notable exception being humans. Its structure, properties and biological role have been reviewed many times.[1][2][3][4][5] BLG is considered to be a milk allergen.[6][7]

Function

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The major protein in whey is β-lactoglobulin, followed by α-lactalbumin (β-lactoglobulin ≈⁠ ⁠65%, α-lactalbumin ≈⁠⁠ ⁠25%, serum albumin ≈⁠⁠ ⁠8%, other ≈⁠ ⁠2%). β-lactoglobulin is a lipocalin protein able to bind many hydrophobic molecules, suggesting its role in their transport. BLG has also been shown to bind molecular iron via siderophores,[8] indicating a possible role in immune pathways combatting pathogens; upon ingestion, BLG can shuttle complexed iron to immune cells, providing micronutrition to the cells, thus participating in overall immune tolerance.[9][10] A human homologue of β-lactoglobulin is lacking in breast milk.[11]

Structure

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Due to its relative abundance in cow's milk and ease of purification, β-lactoglobulin has been the subject of substantial biophysical study; in particular, due to its significance to the food industry - where its physical properties can be either advantageous or disadvantageous to the manufacture and processing of dairy products.[12] The structure of BLG has been circumscribed several times by X-ray crystallography and NMR,[13] with several BLG variants identified, notably the primary bovine variants labelled β-lactoglobulin "A" and "B".

Bovine β-lactoglobulin is a relatively small protein, consisting 162 residues, amounting to18.4 kDa. NMR analysis of BLG in physiological conditions has determined the protein is predominantly dimeric, dissociating to a monomer in acidic environments below pH 3, while preserving its native state.[14] Conversely, BLG also occurs in tetrameric,[15] octameric[16] and other multimeric[17] aggregation forms in a variety of natural conditions.

In solution, β-Lactoglobulin forms gels in several conditions, particularly when its native structure is sufficiently destabilised to allow aggregation.[18] For example, after prolonged heat at low pH and low ionic strength, a transparent `fine-stranded' gel is formed by assembly of protein molecules into long stiff fibres. Folding intermediates of the BLG protein can be studied using light spectroscopy and a denaturing solvent, yielding an unusual but important intermediate composed purely of α-helices - despite its native β-sheet structure. This phenomena is suggested to indicate evolutionary selection for the helical intermediate, avoiding aggregation during the folding process.[19]

β-Lactoglobulin is the main component of milk skin - formed by coagulation and denaturing when milk boils. Once denatured, the BLG proteins form a thin, gelatinous film on the surface of the liquid milk.

Clinical significance

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Due to the allergenic potential of cow's milk (i.e., lactose intolerance),[6] manufacturers in European Union are required to evidence the presence or absence of β-lactoglobulin on labels for food products containing milk to satisfy the requirements of the EC Directive; this is typically determined by food testing laboratories using enzyme linked immunosorbent assay to identify and quantify the BLG in said products.

Although β-lactoglobulin is considered a major allergen, the protective effects of consuming raw cow's milk - namely its ability to transport micronutrients - has been shown to depend on the protein content of the whey fraction, thus of β-lactoglobulin.[20] Studies have shown that BLG carrying micronutrients acted as a tolerogen, protecting against allergy development. However, when micronutrients were absent, BLG acted as an allergen.[21][22][23] Laboratory polymerization of β-lactoglobulin by microbial transglutaminase can reduce its allergenic potential in both children and adults with an IgE-mediated cow's milk allergy.[24]

Biotechnology

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Cow breeding

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In 2018, the first genetically modified cows without β-Lactoglobulin-producing genes were produced by zygotic deletion of the BLG gene locus. Ongoing study aims to produce raw milk without the BLG allergen.[7]

Recombinant production

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In September 2023, the European Innovation Council funded a "Hydrocow" project, by Solar Foods, aiming to produce BLG with the help of Xanthobacter hydrogen-oxidizing bacteria, carbon dioxide and electricity.[25][26]

See also

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References

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  1. ↑ Xiang L, Melton L, Leung KH (2019). "Interactions of β-Lactoglobulin With Small Molecules". In Varelis P, Melton L, Shahidi F (eds.). Encyclopedia of Food Chemistry. Vol. 2. Elsevier. pp. 560–565. doi:10.1016/B978-0-08-100596-5.21488-1. ISBN 978-0-12-814045-1. S2CID 90712856.
  2. ↑ Sawyer L (1992). "Beta-lactoglobulin". In Fox PF, McSweeney PL (eds.). Advanced Dairy Chemistry: 1. Proteins. Elsevier Applied Science. pp. 141–190. doi:10.1007/978-1-4419-8602-3_7. ISBN 978-1-4419-8602-3.
  3. ↑ Sawyer L, Kontopidis G (October 2000). "The core lipocalin, bovine beta-lactoglobulin". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 1482 (1–2): 136–48. doi:10.1016/s0167-4838(00)00160-6. PMID 11058756.
  4. ↑ Kontopidis, George; Holt, Carl; Sawyer, Lindsay (2002). "The Ligand-binding Site of Bovine β-Lactoglobulin: Evidence for a Function?". Journal of Molecular Biology. 318 (4). Elsevier BV: 1043–1055. doi:10.1016/s0022-2836(02)00017-7. ISSN 0022-2836.
  5. ↑ Kontopidis G, Holt C, Sawyer L (April 2004). "Invited review: beta-lactoglobulin: binding properties, structure, and function". Journal of Dairy Science. 87 (4): 785–96. doi:10.3168/jds.S0022-0302(04)73222-1. PMID 15259212.
  6. 1 2 listed in Annex IIIa of Directive 2000/13/EC
  7. 1 2 Wei, Jingwei; Wagner, Stefan; Maclean, Paul; Brophy, Brigid; Cole, Sally; Smolenski, Grant; Carlson, Dan F.; Fahrenkrug, Scott C.; Wells, David N.; Laible, Götz (2018-05-16). "Cattle with a precise, zygote-mediated deletion safely eliminate the major milk allergen beta-lactoglobulin". Scientific Reports. 8 (1): 7661. Bibcode:2018NatSR...8.7661W. doi:10.1038/s41598-018-25654-8. ISSN 2045-2322. PMC 5955954. PMID 29769555.
  8. ↑ Roth-Walter F, Pacios LF, Gomez-Casado C, Hofstetter G, Roth GA, Singer J, et al. (2014-01-01). "The major cow milk allergen Bos d 5 manipulates T-helper cells depending on its load with siderophore-bound iron". PLOS ONE. 9 (8) e104803. Bibcode:2014PLoSO...9j4803R. doi:10.1371/journal.pone.0104803. PMC 4130594. PMID 25117976.
  9. ↑ Roth-Walter F, Afify SM, Pacios LF, Blokhuis BR, Redegeld F, Regner A, et al. (January 2021). "Cow's milk protein β-lactoglobulin confers resilience against allergy by targeting complexed iron into immune cells". The Journal of Allergy and Clinical Immunology. 147 (1): 321–334.e4. doi:10.1016/j.jaci.2020.05.023. hdl:10261/272213. PMID 32485264. S2CID 219285403.
  10. ↑ Afify SM, Pali-Schöll I, Hufnagl K, Hofstetter G, El-Bassuoni MA, Roth-Walter F, Jensen-Jarolim E (2021). "Bovine Holo-Beta-Lactoglobulin Cross-Protects Against Pollen Allergies in an Innate Manner in BALB/c Mice: Potential Model for the Farm Effect". Frontiers in Immunology. 12 611474. doi:10.3389/fimmu.2021.611474. PMC 7977286. PMID 33746954.
  11. ↑ Fiocchi A, Brozek J, Schünemann H, Bahna SL, von Berg A, Beyer K, et al. (April 2010). "World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines". The World Allergy Organization Journal. 3 (4): 57–161. doi:10.1097/WOX.0b013e3181defeb9. PMC 3488907. PMID 23268426.
  12. ↑ Jost R (1993). "Functional characteristics of dairy proteins". Trends in Food Science & Technology. 4 (9): 283–288. doi:10.1016/0924-2244(93)90071-H.
  13. ↑ PDB: 3BLG​; Qin BY, Bewley MC, Creamer LK, Baker HM, Baker EN, Jameson GB (October 1998). "Structural basis of the Tanford transition of bovine beta-lactoglobulin". Biochemistry. 37 (40): 14014–23. doi:10.1021/bi981016t. PMID 9760236.
  14. ↑ Uhrínová S, Smith MH, Jameson GB, Uhrín D, Sawyer L, Barlow PN (April 2000). "Structural changes accompanying pH-induced dissociation of the beta-lactoglobulin dimer". Biochemistry. 39 (13): 3565–74. doi:10.1021/bi992629o. PMID 10736155.
  15. ↑ Timasheff SN, Townend R (1964). "Structure of the β-Lactoglobulin Tetramer". Nature. 203 (4944): 517–519. Bibcode:1964Natur.203..517T. doi:10.1038/203517a0. S2CID 4190604.
  16. ↑ Gottschalk M, Nilsson H, Roos H, Halle B (November 2003). "Protein self-association in solution: the bovine beta -lactoglobulin dimer and octamer". Protein Science. 12 (11): 2404–11. doi:10.1110/ps.0305903. PMC 2366967. PMID 14573854.
  17. ↑ Rizzuti B, Zappone B, De Santo MP, Guzzi R (January 2010). "Native beta-lactoglobulin self-assembles into a hexagonal columnar phase on a solid surface". Langmuir. 26 (2): 1090–5. doi:10.1021/la902464f. PMID 19877696.
  18. ↑ Bromley EH, Krebs MR, Donald AM (2005). "Aggregation across the length-scales in beta-lactoglobulin". Faraday Discussions. 128: 13–27. doi:10.1039/b403014a. PMID 15658764.
  19. ↑ Kuwajima K, Yamaya H, Sugai S (December 1996). "The burst-phase intermediate in the refolding of beta-lactoglobulin studied by stopped-flow circular dichroism and absorption spectroscopy". Journal of Molecular Biology. 264 (4): 806–22. doi:10.1006/jmbi.1996.0678. PMID 8980687.
  20. ↑ Loss G, Apprich S, Waser M, Kneifel W, Genuneit J, Büchele G, et al. (October 2011). "The protective effect of farm milk consumption on childhood asthma and atopy: the GABRIELA study". The Journal of Allergy and Clinical Immunology. 128 (4): 766–773.e4. doi:10.1016/j.jaci.2011.07.048. hdl:1874/407013. PMID 21875744.
  21. ↑ Roth-Walter F, Afify SM, Pacios LF, Blokhuis BR, Redegeld F, Regner A, et al. (January 2021). "Cow's milk protein β-lactoglobulin confers resilience against allergy by targeting complexed iron into immune cells". The Journal of Allergy and Clinical Immunology. 147 (1): 321–334.e4. doi:10.1016/j.jaci.2020.05.023. hdl:10261/272213. PMID 32485264.
  22. ↑ Hufnagl K, Ghosh D, Wagner S, Fiocchi A, Dahdah L, Bianchini R, et al. (January 2018). "Retinoic acid prevents immunogenicity of milk lipocalin Bos d 5 through binding to its immunodominant T-cell epitope". Scientific Reports. 8 (1): 1598. Bibcode:2018NatSR...8.1598H. doi:10.1038/s41598-018-19883-0. PMC 5785490. PMID 29371615.
  23. ↑ Afify SM, Pali-Schöll I, Hufnagl K, Hofstetter G, El-Bassuoni MA, Roth-Walter F, Jensen-Jarolim E (2021). "Bovine Holo-Beta-Lactoglobulin Cross-Protects Against Pollen Allergies in an Innate Manner in BALB/c Mice: Potential Model for the Farm Effect". Frontiers in Immunology. 12 611474. doi:10.3389/fimmu.2021.611474. PMC 7977286. PMID 33746954.
  24. ↑ Olivier CE, Lima RP, Pinto DG, Santos RA, Silva GK, Lorena SL, et al. (October 2012). "In search of a tolerance-induction strategy for cow's milk allergies: significant reduction of beta-lactoglobulin allergenicity via transglutaminase/cysteine polymerization". Clinics. 67 (10): 1171–9. doi:10.6061/clinics/2012(10)09. PMC 3460020. PMID 23070344.
  25. ↑ "Suomalainen yritys aikoo kehittää mikrobin, jolla saadaan maitoa ilman lehmää" [A Finnish company plans to develop a microbe that can produce milk without a cow]. Yle Uutiset (in Finnish). 2023-09-05. Retrieved 2023-10-03.
  26. ↑ "Hydrocow - RWTH AACHEN UNIVERSITY Institut für Angewandte Mikrobiologie - Deutsch". www.iamb.rwth-aachen.de.
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