Primary Information
BoMiProt ID	Bomi116
Protein Name	Lactotransferrin
Organism	Bos taurus
Uniprot ID	P24627
Milk Fraction	Whey
Ref Sequence ID	NP_851341.1
Aminoacid Length	708
Molecular Weight	78056
FASTA Sequence	Download
Gene Name	LTF
Gene ID	280846
Protein Existence Status	Reviewed: Experimental evidence at protein level
Secondary Information
Presence in other biological fluids/tissue/cells	saliva, tears, bile/pncreatic secretions, mucosal secretions of trachea, uterus, ovaries, seminal secretion, plasma, joint fluid
Endogenous/Bioactive peptides - Fragment - Sequence - Effect	Lactoferricin - 17–41/42 - FKCRRWQWRMKKLGAPSICURRAF/A - Antimicrobial Ref
Protein Function	Potent iron chelator; has antimicrobial, anti-tumor, anti-allergeic, anti-inflammatory activities; promotes innante and adaptive immunity and neutrophil migration; depresses endotoxemia; acts as tumor suppressor in multiple cancers; controls oxidative cell injury; inhibits pathological development during autoimmune disorder; prevents cell apoptosis; used as chemotherapeutic agent
Biochemical Properties	Thermostable in acidic environment; optimum pH is 7.5 and temperature is 25°C with 20% α-helix structure; at pH 2-3 structure is partly unfolded with 3% α - helix structure and 54% ß - sheet structure; showed higher thermostability in acidic pH and low ionic strengths; relatively more resistant to heat in acid than in base or neutral solutions ; loses iron binding capacity but retains antimicrobial properties at extreme conditions such as pH 2, 120°C
Significance in milk	Highest in colustrum; has biomodulatory properties and effects nutritional value of the milk; used as active ingredients in infant formula, prebiotic drinks and immune supplements; lactoferrin through pepsin digestion produces a more potent anti-microbial peptide, lactoferrisin that reaches the gut
PTMs	Glycosylated; 5 N-linked glycans; mixtures of high mannose, complex and hybrid type; 59 different structures have been identified till date; fucosylated and sialylated; presence of unusual motifs including N,N'-diacetyllactosamine as found in bovine milk
Site(s) of PTM(s) N-glycosylation, O-glycosylation, Phosphorylation	>sp|P24627|TRFL_BOVIN Lactotransferrin OS=Bos taurus OX=9913 GN=LTF PE=1 SV=2 MKLFVPALLS LGALGLCLAA PRKNVRWCTI SQPEWFKCRR WQWRMKKLGA PSITCVRRAF ALECIRAIAE KKADAVTLDG GMVFEAGRDP YKLRPVAAEI YGTKESPQTH YYAVAVVKKG SNFQLDQLQG RKSCHTGLGR SAGWIIPMGI LRPYLSWTES LEPLQGAVAK FFSASCVPCI DRQAYPNLCQ LCKGEGENQC ACSSREPYFG YSGAFKCLQD GAGDVAFVKE TTVFENLPEK ADRDQYELLC LN*252NSRAPVDA FKECHLAQVP SHAVVARSVD GKEDLIWKLL SKAQEKFGKN KSRSFQLFGS PPGQRDLLFK DSALGFLRIP SKVDSALYLG SRYLTTLKNL RETAEEVKAR YTRVVWCAVG PEEQKKCQQW SQQSGQN*387VTC ATASTTDDCI VLVLKGEADA LNLDGGYIYT AGKCGLVPVL AENRKSSKHS SLDCVLRPTE GYLAVAVVKK ANEGLTWNSL KDKKSCHTAV DRTAGWNIPM GLIVN*495QTGSC AFDEFFSQSC APGADPKSRL CALCAGDDQG LDKCVPNSKE KYYGYTGAFR CLAEDVGDVA FVKN*564DTVWEN TNGESTADWA KNLNREDFRL LCLDGTRKPV TEAQSCHLAV APNHAVVSRS DRAAHVKQVL LHQQALFGKN GKNCPDKFCL FKSETKNLLF NDNTECLAKL GGRPTYEEYL GTEYVTAIAN LKKCSTSPLL EACAFLTR
SCOP	Class : Alpha and beta proteins (a/b) Fold : SBP2HA-like Superfamily : Type 2 solute binding protein-like Family : Transferrin Domain Name : 3IB0 A:342-685
CATH	Matched CATH superfamily 3.40.190.10
Predicted Disorder Regions	NA
DisProt Annotation
TM Helix Prediction	No TM helices
Significance of PTMs	Glycosylation changes at multiple points of lactation; glycosylation plays a role in the protein's bioactivity and its digestion profile in the infant gut; source of novel bioactives; stimulation of bone formation; anticancer; sialylation chelates loosed bound Ca2+ and prevent bacterial colonization
Bibliography	1. Sreedhara, A., Flengsrud, R., Prakash, V., Krowarsch, D., Langsrud, T., Kaul, P., Devold, T. G., and Vegarud, G. E. (2010) A comparison of effects of pH on the thermal stability and conformation of caprine and bovine lactoferrin. Int. Dairy J. 20, 487–494. 2. Kawakami, H., Tanaka, M., Tatsumi, K., and Dosako, S. (1992) Effects of ionic strength and pH on the thermostability of lactoferrin. Int. Dairy J. 2, 287–298. 3. Zimecki, M., Kocieba, M., Chodaczek, G., Houszka, M., and Kruzel, M. L. (2007) Lactoferrin ameliorates symptoms of experimental encephalomyelitis in Lewis rats. J. Neuroimmunol. 182, 160–166. 4. Manzoni, P., Rinaldi, M., Cattani, S., Pugni, L., Romeo, M. G., Messner, H., Stolfi, I., Decembrino, L., Laforgia, N., Vagnarelli, F., Memo, L., Bordignon, L., Saia, O. S., Maule, M., Gallo, E., Mostert, M., Magnani, C., Quercia, M., Bollani, L., Pedicino, R., Renzullo, L., Betta, P., Mosca, F., Ferrari, F., Magaldi, R., Stronati, M., Farina, D., and Italian Task Force for the Study and Prevention of Neonatal Fungal Infections, Italian Society of Neonatology. (2009) Bovine Lactoferrin Supplementation for Prevention of Late-Onset Sepsis in Very Low-Birth-Weight NeonatesA Randomized Trial JAMA 302, 1421. 5. Wang, Y.-Z., Shan, T.-Z., Xu, Z.-R., Feng, J., and Wang, Z.-Q. (2007) Effects of the lactoferrin (LF) on the growth performance, intestinal microflora and morphology of weanling pigs. Anim. Feed Sci. Technol. 135, 263–272. 6. Hua, S., Nwosu, C. C., Strum, J. S., Seipert, R. R., An, H. J., Zivkovic, A. M., German, J. B., and Lebrilla, C. B. (2012) Site-specific protein glycosylation analysis with glycan isomer differentiation. Anal. Bioanal. Chem. 403, 1291–1302. 7. Yoshida, S., Wei, Z., Shinmura, Y., and Fukunaga, N. (2000) Separation of lactoferrin-a and -b from bovine colostrum. J. Dairy Sci. 83, 2211–2215. 8. Debbabi, H., Dubarry, M., Rautureau, M., and Tomé, D. (1998) Bovine lactoferrin induces both mucosal and systemic immune response in mice. J. Dairy Res. 65, 283–293. 9. Kreuß, M., Krause, I., and Kulozik, U. (2009) Influence of glycosylation on foaming properties of bovine caseinomacropeptide. Int. Dairy J. 19, 715–720. 10. Cornish, J., Callon, K. E., Naot, D., Palmano, K. P., Banovic, T., Bava, U., Watson, M., Lin, J.-M., Tong, P. C., Chen, Q., Chan, V. A., Reid, H. E., Fazzalari, N., Baker, H. M., Baker, E. N., Haggarty, N. W., Grey, A. B., and Reid, I. R. (2004) Lactoferrin Is a Potent Regulator of Bone Cell Activity and Increases Bone Formation in Vivo. Endocrinology 145, 4366–4374. 11. Ujita, M., Furukawa, K., Aoki, N., Sato, T., Noda, A., Nakamura, R., Greenwalt, D. E., and Matsuda, T. (1993) A change in soybean agglutinin binding patterns of bovine milk fat globule membrane glycoproteins during early lactation. FEBS Lett. 332, 119–122. 12. Wang, B., Yu, B., Karim, M., Hu, H., Sun, Y., McGreevy, P., Petocz, P., Held, S., and Brand-Miller, J. (2007) Dietary sialic acid supplementation improves learning and memory in piglets. Am. J. Clin. Nutr. 85, 561–569. 13. Takimori, S., Shimaoka, H., Furukawa, J.-I., Yamashita, T., Amano, M., Fujitani, N., Takegawa, Y., Hammarström, L., Kacskovics, I., Shinohara, Y., and Nishimura, S.-I. (2011) Alteration of the N-glycome of bovine milk glycoproteins during early lactation. FEBS J. 278, 3769–3781. 14. van Leeuwen, S. S., Schoemaker, R. J. W., Timmer, C. J. A. M., Kamerling, J. P., and Dijkhuizen, L. (2012) Use of Wisteria floribunda agglutinin affinity chromatography in the structural analysis of the bovine lactoferrin N-linked glycosylation. Biochim. Biophys. Acta - Gen. Subj. 1820, 1444–1455. 15. O’Riordan, N., Gerlach, J. Q., Kilcoyne, M., O’Callaghan, J., Kane, M., Hickey, R. M., and Joshi, L. (2014) Profiling temporal changes in bovine milk lactoferrin glycosylation using lectin microarrays. Food Chem. 165, 388–396. 16. Puddu, P., Latorre, D., Carollo, M., Catizone, A., Ricci, G., Valenti, P., and Gessani, S. (2011) Bovine lactoferrin counteracts Toll-like receptor mediated activation signals in antigen presenting cells. PLoS One 6, e22504. 17. He, Y., Lawlor, N. T., and Newburg, D. S. (2016) Human Milk Components Modulate Toll-Like Receptor-Mediated Inflammation. Adv. Nutr. 7, 102–111. 18. He, S., McEuen, A. R., Blewett, S. A., Li, P., Buckley, M. G., Leufkens, P., and Walls, A. F. (2003) The inhibition of mast cell activation by neutrophil lactoferrin: uptake by mast cells and interaction with tryptase, chymase and cathepsin G. Biochem. Pharmacol. 65, 1007–1015. 19. Schaible, U. E., Collins, H. L., Priem, F., and Kaufmann, S. H. E. (2002) Correction of the iron overload defect in beta-2-microglobulin knockout mice by lactoferrin abolishes their increased susceptibility to tuberculosis. J. Exp. Med. 196, 1507–1513. 20. Bullen, J. J., Rogers, H. J., and Leigh, L. (1972) Iron-binding proteins in milk and resistance to Escherichia coli infection in infants. Br. Med. J. 1, 69–75. 21. Reiter, B., Brock, J. H., and Steel, E. D. (1975) Inhibition of Escherichia coli by bovine colostrum and post-colostral milk. II. The bacteriostatic effect of lactoferrin on a serum susceptible and serum resistant strain of E. coli. Immunology 28, 83–95. 22. Spik, G., Cheron, A., Montreuil, J., and Dolby, J. M. (1978) Bacteriostasis of a milk-sensitive strain of Escherichia coli by immunoglobulins and iron-binding proteins in association. Immunology 35, 663–671. 23. Masson, P. L., Heremans, J. F., Prignot, J. J., and Wauters, G. (1966) Immunohistochemical localization and bacteriostatic properties of an iron-binding protein from bronchial mucus. Thorax 21, 538–544. 24. 1. Bertuccini, L., Costanzo, M., Iosi, F., Tinari, A., Terruzzi, F., Stronati, L., Aloi, M., Cucchiara, S., and Superti, F. (2014) Lactoferrin prevents invasion and inflammatory response following E. coli strain LF82 infection in experimental model of Crohn’s disease. Dig. Liver Dis. 46, 496–504. 25. Yoo, Y. C., Watanabe, S., Watanabe, R., Hata, K., Shimazaki, K., and Azuma, I. (1997) Bovine lactoferrin and lactoferricin, a peptide derived from bovine lactoferrin, inhibit tumor metastasis in mice. Jpn. J. Cancer Res. 88, 184–190. 26. Janssen, P. T. and van Bijsterveld, O. P. (1983) Origin and biosynthesis of human tear fluid proteins. Invest. Ophthalmol. Vis. Sci. 24, 623–630. 27. Saito, K. and Nakanuma, Y. (1992) Lactoferrin and lysozyme in the intrahepatic bile duct of normal livers and hepatolithiasis. An immunohistochemical study. J. Hepatol. 15, 147–153. 28. Varadhachary, A., Wolf, J. S., Petrak, K., O’Malley, B. W., Spadaro, M., Curcio, C., Forni, G., and Pericle, F. (2004) Oral lactoferrin inhibits growth of established tumors and potentiates conventional chemotherapy. Int. J. Cancer 111, 398–403. 29. Saito, H., Miyakawa, H., Tamura, Y., Shimamura, S., and Tomita, M. (1991) Potent Bactericidal Activity of Bovine Lactoferrin Hydrolysate Produced by Heat Treatment at Acidic pH. J. Dairy Sci. 74, 3724–3730. 30. Zhang, J., Ling, T., Wu, H., and Wang, K. (2015) Re-expression of Lactotransferrin , a candidate tumor suppressor inactivated by promoter hypermethylation, impairs the malignance of oral squamous cell carcinoma cells. J. Oral Pathol. Med. 44, 578–584