Lactoferrin polypeptide folding

As noted above, the two lobes have very similar folding. This is only to be expected given their high (—40%) sequence identity. The differences, at the level of polypeptide folding, are confined primarily to small insertions and deletions in the loops that join secondary structure elements. These are almost all located on the molecular surface and do not disturb the basic structure—indeed 90% of the main chain atoms of the N-lobe of human lactoferrin can be superimposed on equivalent atoms in the C-lobe with a root-mean-square deviation of only —1.2 A. The agreement would be even closer were it not for the small difference in the closure of the two domains, described above. 

Fig. 5. Polypeptide folding pattern found in each lobe of human lactoferrin. Helices (cylinders) are numbered 1 to 12 and /3-strands (arrows) are labeled a to k as in Anderson et al. (78). The interdomain backbone strands are shaded and the position of the hinge is indicated.

Most remarkably, one group of the bacterial binding proteins, which includes the two anion-binding proteins so far analyzed [specific for sulfate (115) and phosphate (116)], has even closer similarity. First, the polypeptide folding pattern in these proteins is almost identical to that in each lobe of lactoferrin (Fig. 15) the central /3-sheet of each... 

Fig. 15. Polypeptide folding patterns for (a) one-half of a transferrin molecule (the N-lobe of lactoferrin) and (b) the bacterial periplasmic sulfate-binding protein. Adapted from Baker et al. (85), with permission.

Figure 5.8 A schematic representation of the N-lobe polypeptide chain fold, showing the conformational change between open and closed forms of human lactoferrin. Reprinted with permission from Nature (Anderson et ah, 1990). Copyright (1990) Macmillan Magazines Limited.

All transferrins characterized so far consist of a single polypeptide chain of 670-700 amino acid residues. The lactoferrin and serum transferrin structure analyses show that the folding (polypeptide chain conformation) is the same in both proteins and, given their sequence homology, can be assumed to hold for all proteins of the transferrin family. 

The polypeptide chain is first of all folded into two globular lobes, representing the N-terminal and C-terminal halves of the molecule these are referred to as the N-lobe and C-lobe, respectively. In human lactoferrin the N-lobe comprises residues 1-333 and the C-lobe, residues 345-691, whereas in rabbit serum transferrin the equivalent lobes comprise 1-328 and 342-676. Each lobe contains a single iron binding site, and each has essentially the same folding (described more fully in Section III.B.2). The two lobes do not have equivalent orientations... 

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