How do trypanosome receptors bind transferrin?
Why do trypanosomes have a family of transferrin receptors?
In the latest discovery from our collaboration with Professor Mark Carrington, Camilla Trevor determined how the transferrin receptor, found within the densely packed coat of the trypanosome surface, binds to transferrin and investigated why these parasites have a family of transferrin receptors.
Trypanosomes infect mammals and live within their blood. They harvest transferrin from their surroundings using the transferrin receptor to recognise this iron-packed nutrient. While trypanosomes are thought to have a single receptor for most nutrients, they have a panel of transferrin receptors available for deployment. Why is this? A long-standing theory is that it allows trypanosomes to infect a wide range of different mammals which have different transferrin molecules.
Camilla was able to determine the structure of the trypansome transferrin receptor bound to transferrin, revealing that the receptor presents a large, flat surface at its tip, to which transferrin binds. However, surprisingly she found that the regions of the receptor which contact transferrin do not vary across the family of receptors making it unlikely that variation occurs in order to allow differences in transferrin binding. Indeed, she was able to find transferrin receptors which could bind to transferrin molecules from a wide range of mammals.
Instead, the evidence suggests that trypanosomes have a family of transferrin receptors to allow them to hide from the immune system. Parasites such as the trypanosomes, which must grow and survive within human blood, often use a trick known as antigenic variation. As they are recognised by the immune system, they switch the molecules of their surface coat, allowing them to hide. The pattern of variation found in the trypanosome transferrin receptor, in which variation and flexible glycans are concentrated in regions of the receptor which are most exposed to the immune system, is consistent with the parasite retaining a family of transferrin receptors to allow it to continue to harvest nutrients while hiding from detection.
The transferrin receptor family is therefore another example of how parasite switch their surface to stay hidden while allowing them to continue to exploit their mammalian hosts.
Trevor, C., Gonzalez-Munoz, A.L., MacLeod, O.J.S., Woodcock, P.G., Rust, S., Vaughan, T.J., Garman, E.F., Minter, R., Carrington, M.* and Higgins, M.K.* (2019) Structure of the trypanosome transferrin receptor reveals mechanisms of ligand recognition and immune evasion. Nature Microbiology 4 2074-81 (* joint corresponding)
