A structural framework for understanding the multifunctional character of lactoferrin.
Lactoferrin (Lf) is widely distributed, in mammalian milks, other secretory fluids and white blood cells, and its biology is complex. The three-dimensional structure of this important protein was determined in 1987, giving the first atomic view of any member of the transferrin family. This review examines how structural knowledge has contributed to our understanding of Lf function, and what we have yet to understand. The internal structure of Lf is highly conserved, and is dedicated to binding iron, which is sequestered in two almost identical sites, one in each lobe of the molecule. The processes of iron binding and release, and the accompanying conformational changes, are well understood. Some functional properties of Lf derive from this property, both through iron scavenging, and because the structure and dynamics of Lf are altered by its iron status. On the other hand, the external structure (its molecular surface) is much more variable between different Lfs, making it more difficult to identify functionally important sites. One key feature is clear - the cationic N-terminus and associated lactoferricin domain on the N-lobe of Lf. Recent work shows that this region, in addition to its role in antibacterial activity and probable role in DNA binding, is also involved in complex formation with other proteins. Other parts of the surface are more variable and may result in functional differences between the Lfs of different species. Finally, it may be time to re-examine the importance of glycosylation, given the growing evidence that many pathogens depend on binding to glycans for pathogenesis.
Baker
Edward N
EN
School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand. ted.baker@auckland.ac.nz
Baker
Heather M
HM
D000818:Animals; D006801:Humans; D007501:Iron / Q000378:metabolism; D007781:Lactoferrin / Q000737:chemistry* / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
D007501:Iron; D007781:Lactoferrin