If asked to name the most prevalent inherited diseases, most people would probably suggest cystic fibrosis, sickle cell anaemia or haemophilia. Few would even have heard of hereditary haemochromatosis. But this disease, characterized by the uptake of too much iron into a sufferer's body, affects one in every three hundred Caucasians, and one in nine is a carrier.
Iron is crucial for the working of haemoglobin, the red pigment in blood that carries oxygen from the lungs to all other parts of the body. But too much iron can be as disabling as too little. In hereditary haemochromatosis deposits of iron appear in practically every major organ, particularly the liver, pancreas and heart, resulting in complete and widespread organ failure.
Hereditary haemochromatosis is caused by mutations in a protein known by the acronym 'HFE', but the normal functioning of this protein remains unclear. Now Pamela Bjorkman and colleagues of the California Institute of Technology give us some clues by showing how HFE binds to another protein, the 'transferrin receptor', which is more directly involved in moving iron into cells.
Like all metals, iron is insoluble in water, so in the blood stream it is transported by a carrier protein called transferrin. Cells absorb this solubilized iron using a protein called the transferrin receptor, which is attached to their surfaces. As its name implies, this molecule binds to transferrin, dragging it into the cell where the iron is removed. Empty transferrin is then ejected into the blood stream to pick up more iron. HFE is also present on cell membranes, where it can bind to the transferrin receptor. Its presence does not affect the ability of iron-bearing transferrin to stick to the receptor; but it does prevent empty transferrin from attaching.
The individual structures of the transferrin receptor and HFE are already known. What Bjorkman and colleagues now give us in
But what does this glimpse show? We see two molecules of the transferrin receptor joined together in the centre, with two HFE molecules binding to opposite sides of this 'core'. HFE appears to lie against the cell's surface so that it can bind to the transferrin receptor close to the cell membrane, without obstructing the workings of the receptor.
Despite binding a considerable distance from where transferrin is thought to attach, HFE has a profound affect on the attachment region of the transferrin receptor. It causes large movements of the two transferrin receptor molecules, as well as rearrangements within each molecule. This closes a cleft in the transferrin receptor where transferrin is thought to bind. These changes are almost certainly responsible for changes in the transferrin receptor's ability to bind transferrin in the presence of HFE.
As is so often the case with the structures of biological molecules, these results are at once revealing and enigmatic. Both the transferrin receptor and HFE span the cell's membrane, so structural changes like those seen here could be used by proteins within the cell to monitor the status of the receptor. Or perhaps HFE simply uses the transferrin receptor as a way of entering the cell in times of iron glut, hitchhiking on the larger molecule to regions where it can find other binding partners and thus affect iron metabolism.
Whatever the precise role of HFE, Bjorkman and her collaborators have revealed, in exquisite detail, the interactions between this fascinating protein and the transferrin receptor. Somewhere within this co-operative activity lies the key to the cause of one of mankind's commonest 'construction faults'.