A Tour of Transferrin


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Transferrins are the proteins responsible for the transport of iron into the cells of higher organisms. The members of this family are serum transferrin (found in blood serum), ovotransferrin (found in eggs) and lactotransferrin (a constituent of milk). All of them have remarkably similar overall structure with a mass of about 80 kDa and approximately 700 amino acid residues. They are glycoproteins but the sugar group is not shown in the structure of this tour. Transferrin not only acts as an iron carrier, but also functions as an Fe scavenger keeping the concentration of free iron at a low value. It therefore functions to deprive bacteria of Fe so they cannot grow. [1] Serum transferrins shuttle iron from the liver to bone marrow cells where hemoglobin is produced. The structure of porcine serum transferrin is shown on the left.

Transferrin consists of two lobes: the N lobe (white) and the C lobe (blue). Each contains 11 beta strands and 16 alpha helices. This secondary structure makes the protein very flexible. The importance of this flexibility will be discussed below. The amino acid sequence of the two lobes is quite similar.

Both lobes contain two domains that are separated by a hinge region. The N lobe has the NI (grey) and NII (white) domains and the C lobe has the CI (blue) and CII (greenish blue) domains. Each lobe can accommodate one iron ion (orange), each in conjunction with a carbonate ion (not shown on this display). These ions are located deep in the cavity formed by the lobe’s two domains. Since the lobes have a similar sequence and the same iron binding site, we will only concentrate on the N lobe.

The iron(III) "sits" in an octahedral coordination site inside the lobe. Four residues from the protein (Tyr94, Tyr192, His253 and Asp62) and a bidentate (CO3)2- coordinate to the iron. The water molecule HOH59 (only the oxygen is shown) hydrogen-bonds to the oxygen of Tyr94. Click to see the coordination polyhedron more clearly.

The hydrogen bonds formed between (CO3)2- and the residues located in the NII domain keep the protein wrapped tightly around the iron. For simplicity, the side chain residues that coordinate the Fe are represented by their donor atoms only. The O1 atom from the carbonate ligand is H-bonded to the -OH group on Thr119 and to the NH group on Gly126. Ala 125 hydrogen bonds to the O2 atom of the (CO3)2-. The remaining oxygen, O1, of the (CO3)2- forms two O..H-N hydrogen bonds with Arg123.

There is the evidence that two lysine residues Lys210 and Lys300, located in the NI domain of the N lobe might be responsible for triggering the release of the iron. In iron-loaded transferrin, one lysine side chain is in the protonated, NH3+ form while the other is in the neutral, NH2 form and these form an N-H..N hydrogen bond.

The iron-loaded transferrin enters the cell by endocytosis. Once inside, this endosome is acidified to pH 5[2], and the transferrin releases the iron ions. The unprotonated amino group of the lysine trigger is now protonated and the lysine ammonium groups repel each other, causing an opening of the protein. This allows the protonation of the (CO3)2- group and His253 and the subsequent release of the iron ion.[3] (Interestingly, this "dilysine trigger" does not exist in the C lobe. This might explain the fact that the N lobe releases its Fe more easily than the C lobe.)

In apo-transferrin, the two domains open up into a 'V' - shaped conformation ('Venus Flytrap' or 'PacMan') and are ready to trap the iron inside. The residues that coordinate to the iron(III) are shown in green. They are located on different domains and are separated by approximately 10 ang. The residues that form hydrogen bonds with (CO3)2- (magenta) are also on the opposite sides.

Transferrin picks up the iron and carbonate outside of the cell at the pH value of 7.4 as Fe(II). Oxygen then oxidizes Fe(II) to Fe(III): [4]

[(Fe2+)Tf(CO3)2- ]+O2 arrows (1K) [(Fe3+)Tf(CO3)2- ]+ O2-

(Tf = transferrin)

Large conformation changes in the protein occur upon the iron uptake. The distance between the lobe domains shortens by about 15 ang. This significant change in the protein geometry is possible due to the flexibility of the hinge region. Also, the "gate" is closed.

Here is the N-lobe of transferrin to explore further on your own.


Crystal structure of porcine serum transferrin reported in Hall, D.R. et al., Acta Cryst. Sec. D. (2002), D58, 70-80 (PDB ID 1H76) Crystal structure of apotransferrin reported in Hall, D.R. et al., Acta Cryst. Sec. B. (1991), B47, 998 (PDB ID 1LFH).



div101 (1K)

[1] For example, only about 30% of the iron sites in the human plasma transferrin are occupied. The rest serve as "iron scavenger".

[2] For the lactoferrins this pH value is lower.

[3] Usually lysine sidechains are in the protonated form with pKa 10.4. However, in the case of the lysine trigger, the hydrogen-bonded lysine amino group has a lower pKa and so it is only protonated at pH values less than 6.

[4] The side product of this reaction, superoxide ion O2-, is a very reactive species that can easily damage the cell. In order to protect itself from superoxide, nature has devised a special metalloprotein - superoxide dismutase (SOD). SOD is also part of The Guided Tour of Metalloproteins.

Copyright Robert H. Morris and Alen Hadzovic, 1998, 2006, 2011, 2017.