Beta-lactoglobulin explained

Uniprot:P02754
Symbol:BLG
Organism:Bos taurus

β-Lactoglobulin (BLG) 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] BLG is considered to be a milk allergen.[5]

Function

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, and can bind many hydrophobic molecules, suggesting a role in their transport. β-lactoglobulin has also been shown to be able to bind iron via siderophores[6] and thus might have a role in combating pathogens. Upon ingestion BLG is able to shuttle complexed iron into human immune cells, thereby providing micronutrition to these cells and participating in immune tolerance.[7] [8] A homologue of β-lactoglobulin is lacking in human breast milk.[9]

Structure

Several variants have been identified, the main ones in the cow being labelled A and B. Because of its abundance and ease of purification, it has been subjected to a wide range of biophysical studies. Its structure has been determined several times by X-ray crystallography and NMR.[10] β-lactoglobulin is of direct interest to the food industry since its properties can variously be advantageous or disadvantageous in dairy products and processing.[11]

Bovine β-lactoglobulin is a relatively small protein of 162 residues, with an 18.4 kDa. In physiological conditions it is predominantly dimeric, but dissociates to a monomer below about pH 3, preserving its native state as determined by using NMR.[12] Conversely, β-lactoglobulin also occurs in tetrameric,[13] octameric[14] and other multimeric[15] aggregation forms under a variety of natural conditions.

β-Lactoglobulin solutions form gels in various conditions, when the native structure is sufficiently destabilised to allow aggregation.[16] Under prolonged heating at low pH and low ionic strength, a transparent `fine-stranded' gel is formed, in which the protein molecules assemble into long stiff fibres.

β-Lactoglobulin is the main component of milk skin, coagulating and denaturing when the milk boils. Once denatured, the β-Lactoglobulin forms a thin gelatinous film on the surface of the milk.

Folding intermediates for this protein can be studied using light spectroscopy and denaturant. Such experiments show an unusual but important intermediate composed purely of alpha helices, despite the fact that the native structure is beta sheet. Evolution has probably selected for the helical intermediate to avoid aggregation during the folding process.[17]

Clinical significance

As milk is a known allergen,[18] manufacturers in European Union need to prove the presence or absence of β-lactoglobulin to ensure their labelling satisfies the requirements of the EC Directive. Food testing laboratories can use enzyme linked immunosorbent assay methods to identify and quantify β-lactoglobulin in food products.Though β-lactoglobulin is considered a major allergen, the protective impact of the consumption of raw milk has been shown to dependent on the protein-content of the whey fraction and thus of β-lactoglobulin.[19] This great contrast, on the one hand an allergen and on the other protective, has now been linked with its ability to carry micronutrient. When β-lactoglobulin carried micronutrient it acted tolerogenic and protected against allergy development. However, when the loading was missing, it turned into an allergen.[20] [21] [22]

Laboratory polymerization of β-lactoglobulin by microbial transglutaminase reduces its allergenicity in children and adults with an IgE-mediated cow’s milk allergy.[23]

Cows breeding

In 2018 it was announced that genetically modified cows were grown. The cows had their β-Lactoglobulin producing genes removed by a zygote-mediated deletion process.

See also

Notes and References

  1. Book: Xiang L, Melton L, Leung KH . Varelis P, Melton L, Shahidi F . Encyclopedia of Food Chemistry . Elsevier . 2019 . 2 . 560–565 . Interactions of β-Lactoglobulin With Small Molecules . 9780128140451 . 10.1016/B978-0-08-100596-5.21488-1 . 90712856 .
  2. Book: Sawyer L . Beta-lactoglobulin . Fox PF, McSweeney PL . Advanced Dairy Chemistry: 1. Proteins . 1992 . Elsevier Applied Science . 141–190 . 10.1007/978-1-4419-8602-3_7 . 978-1-4419-8602-3 .
  3. Sawyer L, Kontopidis G . The core lipocalin, bovine beta-lactoglobulin . Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology . 1482 . 1–2 . 136–48 . October 2000 . 11058756 . 10.1016/s0167-4838(00)00160-6 .
  4. Kontopidis G, Holt C, Sawyer L . Invited review: beta-lactoglobulin: binding properties, structure, and function . Journal of Dairy Science . 87 . 4 . 785–96 . April 2004 . 15259212 . 10.3168/jds.S0022-0302(04)73222-1 . free .
  5. 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 . 10.1038/s41598-018-25654-8 . 2045-2322 . 5955954 . 29769555. 2018NatSR...8.7661W .
  6. Roth-Walter F, Pacios LF, Gomez-Casado C, Hofstetter G, Roth GA, Singer J, Diaz-Perales A, Jensen-Jarolim E . 6 . 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 . 2014-01-01 . 25117976 . 4130594 . 10.1371/journal.pone.0104803 . free . 2014PLoSO...9j4803R .
  7. Roth-Walter F, Afify SM, Pacios LF, Blokhuis BR, Redegeld F, Regner A, Petje LM, Fiocchi A, Untersmayr E, Dvorak Z, Hufnagl K, Pali-Schöll I, Jensen-Jarolim E . 6 . 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 . January 2021 . 32485264 . 10.1016/j.jaci.2020.05.023 . 219285403 . free . 10261/272213 . free .
  8. Afify SM, Pali-Schöll I, Hufnagl K, Hofstetter G, El-Bassuoni MA, Roth-Walter F, Jensen-Jarolim E . 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 . 2021 . 33746954 . 7977286 . 10.3389/fimmu.2021.611474 . free .
  9. Fiocchi A, Brozek J, Schünemann H, Bahna SL, von Berg A, Beyer K, Bozzola M, Bradsher J, Compalati E, Ebisawa M, Guzman MA, Li H, Heine RG, Keith P, Lack G, Landi M, Martelli A, Rancé F, Sampson H, Stein A, Terracciano L, Vieths S . 6 . 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 . April 2010 . 23268426 . 3488907 . 10.1097/WOX.0b013e3181defeb9 .
  10. Qin BY, Bewley MC, Creamer LK, Baker HM, Baker EN, Jameson GB . Structural basis of the Tanford transition of bovine beta-lactoglobulin . Biochemistry . 37 . 40 . 14014–23 . October 1998 . 9760236 . 10.1021/bi981016t .
  11. Jost R . 1993 . Functional characteristics of dairy proteins. . Trends in Food Science & Technology . 4 . 9 . 283–288 . 10.1016/0924-2244(93)90071-H .
  12. Uhrínová S, Smith MH, Jameson GB, Uhrín D, Sawyer L, Barlow PN . Structural changes accompanying pH-induced dissociation of the beta-lactoglobulin dimer . Biochemistry . 39 . 13 . 3565–74 . April 2000 . 10736155 . 10.1021/bi992629o .
  13. Timasheff SN, Townend R . 1964 . Structure of the β-Lactoglobulin Tetramer . Nature . 203 . 4944 . 517–519 . 10.1038/203517a0 . 1964Natur.203..517T . 4190604 .
  14. Gottschalk M, Nilsson H, Roos H, Halle B . Protein self-association in solution: the bovine beta -lactoglobulin dimer and octamer . Protein Science . 12 . 11 . 2404–11 . November 2003 . 14573854 . 2366967 . 10.1110/ps.0305903 .
  15. Rizzuti B, Zappone B, De Santo MP, Guzzi R . Native beta-lactoglobulin self-assembles into a hexagonal columnar phase on a solid surface . Langmuir . 26 . 2 . 1090–5 . January 2010 . 19877696 . 10.1021/la902464f .
  16. Bromley EH, Krebs MR, Donald AM . Aggregation across the length-scales in beta-lactoglobulin . Faraday Discussions . 128 . 13–27 . 2005 . 15658764 . 10.1039/b403014a .
  17. Kuwajima K, Yamaya H, Sugai S . 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 . December 1996 . 8980687 . 10.1006/jmbi.1996.0678 .
  18. listed in Annex IIIa of Directive 2000/13/EC
  19. Loss G, Apprich S, Waser M, Kneifel W, Genuneit J, Büchele G, Weber J, Sozanska B, Danielewicz H, Horak E, van Neerven RJ, Heederik D, Lorenzen PC, von Mutius E, Braun-Fahrländer C . 6 . 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 . October 2011 . 21875744 . 10.1016/j.jaci.2011.07.048 . 1874/407013 . free .
  20. Roth-Walter F, Afify SM, Pacios LF, Blokhuis BR, Redegeld F, Regner A, Petje LM, Fiocchi A, Untersmayr E, Dvorak Z, Hufnagl K, Pali-Schöll I, Jensen-Jarolim E . 6 . 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 . January 2021 . 32485264 . 10.1016/j.jaci.2020.05.023 . free . 10261/272213 . free .
  21. Hufnagl K, Ghosh D, Wagner S, Fiocchi A, Dahdah L, Bianchini R, Braun N, Steinborn R, Hofer M, Blaschitz M, Roth GA, Hofstetter G, Roth-Walter F, Pacios LF, Jensen-Jarolim E . 6 . Retinoic acid prevents immunogenicity of milk lipocalin Bos d 5 through binding to its immunodominant T-cell epitope . Scientific Reports . 8 . 1 . 1598 . January 2018 . 29371615 . 5785490 . 10.1038/s41598-018-19883-0 . 2018NatSR...8.1598H .
  22. Afify SM, Pali-Schöll I, Hufnagl K, Hofstetter G, El-Bassuoni MA, Roth-Walter F, Jensen-Jarolim E . 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 . 2021 . 33746954 . 7977286 . 10.3389/fimmu.2021.611474 . free .
  23. Olivier CE, Lima RP, Pinto DG, Santos RA, Silva GK, Lorena SL, Villas-Boas MB, Netto FM, Zollner R . 6 . 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 . October 2012 . 23070344 . 3460020 . 10.6061/clinics/2012(10)09 .

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