The structure of the trypanosome haptoglobin-haemoglobin receptor

How do receptor proteins function in the densely packed coat of an African trypanosome?

African trypanosomes, the causative agents of the cattle disease nagana and of human sleeping sickness, live free in the blood of an infected mammal. To evade detection by the mammalian immune system, they have evolved a remarkable surface coat, densely packed with many copies of the VSG molecule. How do receptor proteins operate within this coat?

In a close collaboration with Mark Carrington’s group, Harriet Lane-Serff tackled this question by focusing on the haptoglobin-haemoglobin receptor. This receptor plays an important role in nutrient uptake, allowing trypanosomes to scavenge haem-rich haemoglobin from its environment. However, it also provides a route by which a toxin, the trypanolytic complex, enters trypanosomes, leading to their death.

Harriet was able to determine the structure of the haptoglobin-haemoglobin receptor from Trypanosoma brucei bound to a monomeric form of its ligand. This revealed the nature of the ligand binding site, and also revealed a kink in the receptor. This kink will hold apart the VSG molecules surrounding the receptor, keeping its binding site open in the context of the VSG layer.

Haptoglobin-haemoglobin in the blood assembles into a dimer and modelling the dimeric complex revealed a second reason for the kink, showing that it will allow two membrane-attached receptors to simultaneously bind to a single haptoglobin-haemoglobin dimer. Indeed, Paula McGregor showed that trypanosomes more efficiently take up dimeric haptoglobin-haemoglobin than monomeric.

This study therefore reveals the first structure of a trypanosome receptor bound to its ligand and reveals adaptations that allow it to operate in the context of the VSG layer.

Lane-Serff, H., McGregor, P., Lowe, E.D., Carrington, M.* and Higgins, M.K.* (2014) Structural basis for ligand and innate immunity factor uptake by the trypanosome haptoglobin-haemoglobin receptor. eLife 3 e05553