Amino-Terminal Half-Molecule of Human Lactoferrin

Human lactoferrin, LF, is a protein in the transferrin family. As such, it has the ability to tightly bind iron in conjunction with a large-scale conformational change associated with iron binding and release.^[1] These properties give lactoferrin the ability to regulate iron, and possibly other metal, ion levels in the fluids and secretions, such as milk, of animals.^[1] Lactoferrin is folded into two lobes: the N-terminal half, LF_N (1dsn), and the C-terminal half, LF_C. The two LF lobes have 37% homology and very similar tertiary structures; it has been suggested that the two lobes are the product of gene duplication.^[2] Each lobe of LF_N is further subdivided into two similarly sized α and β domains (Figure 1); the is situated in a deep cleft between the two domains.^[1]

In humans, lactoferrin is most abundant in milk, where it acts as part of the innate immune system.^[3]

Structure

Figure 1. Cartoon illustrating the alpha (green) and beta (magenta) domains of LF_N

The amino-terminal half-molecule of human lactoferrin (LF_N) is comprised of a single 333 amino acid chain divided into two similarly-sized α and β domains. The iron binding site is located within a deep cleft between the lobes, where iron is bound by of the α and β domains, respectively. Iron, which is bound to a carboxylate ion, is bound by Asp60, Ala123, and Gly124. Although unwound in LF_N, form a helix when joined to LF_C, forming the full LF protein.^[1]

The structure of LF_N undergoes a dramatic conformational change upon iron binding. Upon iron binding, the two domains of LF_N undergo a rigid 54.1º rotation about a that passes through Thr90 and Pro251.^[4]

Function & Application

Like transferrin, lactoferrin is an iron binding molecule, capable of regulating iron levels in bodily fluids and secretions.^[1] Unlike transferrin, only trace amounts of lactoferrin are found serum; however, lactoferrin can be found on concentrations ranging from 1 g/L to 7 g/L in milk.^[3] In human milk, lactoferrin is a part of the innate immune system, demonstrating anti-microbial properties.^[3][2] Many of lactoferrin's anti-microbial effects come from its ability to sequester iron, necessary for microbial growth.^[2] Lactoferrin also exhibits anti-viral activity by binding to the key viral features of several viruses including hepatitis c virus, rotavirus, poliovirus, and HIV.^[5]

Because of the intrinsic antiviral properties of lactoferrin, it is of great interest as a drug delivery molecule. In this system, traditional antiviral medication, that can normally lead to a wide range of side-effects, can be targeted using lactoferrin, mitigating any ill effects.^[5]

External Resources

Lactoferrin at Wikipedia

3D structures of human lactoferrin

Lactoferrin

References

1. ↑ ^{1.0 1.1 1.2 1.3 1.4} Faber HR, Bland T, Day CL, Norris GE, Tweedie JW, Baker EN. Altered domain closure and iron binding in transferrins: the crystal structure of the Asp60Ser mutant of the amino-terminal half-molecule of human lactoferrin. J Mol Biol. 1996 Feb 23;256(2):352-63. PMID:8594202
2. ↑ ^{2.0 2.1 2.2} Farnaud S, Evans RW. Lactoferrin--a multifunctional protein with antimicrobial properties. Mol Immunol. 2003 Nov;40(7):395-405. PMID:14568385
3. ↑ ^{3.0 3.1 3.2} Sanchez L, Calvo M, Brock JH. Biological role of lactoferrin. Arch Dis Child. 1992 May;67(5):657-61. PMID:1599309
4. ↑ Gerstein M, Anderson BF, Norris GE, Baker EN, Lesk AM, Chothia C. Domain closure in lactoferrin. Two hinges produce a see-saw motion between alternative close-packed interfaces. J Mol Biol. 1993 Nov 20;234(2):357-72. PMID:8230220 doi:http://dx.doi.org/10.1006/jmbi.1993.1592
5. ↑ ^{5.0 5.1} van der Strate BW, Beljaars L, Molema G, Harmsen MC, Meijer DK. Antiviral activities of lactoferrin. Antiviral Res. 2001 Dec;52(3):225-39. PMID:11675140

Page originally authored by Christian Axen