Beyond the VSG Layer: Exploring the Role of Intrinsic Disorder in the Invariant Surface Glycoproteins of African Trypanosomes

In the bloodstream of mammalian hosts, African trypanosomes face the challenge of protecting their invariant surface receptors from immune detection. This crucial role is fulfilled by a dense, glycosylated protein layer composed of variant surface glycoproteins (VSGs), which undergo antigenic variation and provide a physical barrier that shields the underlying invariant surface glycoproteins (ISGs). The protective shield's limited permeability comes at the cost of restricted access to the extracellular host environment, raising questions regarding the specific function of the ISG repertoire. In this study, we employ an integrative structural biology approach to show that intrinsically disordered membrane-proximal regions are a common feature of members of the ISG super-family, conferring the ability to switch between compact and elongated conformers. While the folded, membrane-distal ectodomain is buried within the VSG layer for compact conformers, their elongated counterparts would enable the extension beyond it. This dynamic behavior enables ISGs to maintain a low immunogenic footprint while still allowing them to engage with the host environment when necessary. Our findings add further evidence to a dynamic molecular organization of trypanosome surface antigens wherein intrinsic disorder underpins the characteristics of a highly flexible ISG proteome to circumvent the constraints imposed by the VSG coat. In the blood of their human and animal hosts, single-celled parasites of the species Trypanosoma brucei need to hide from the body's defense system to survive. These parasites have a special armor made of proteins (known as VSGs) that changes regularly, helping them stay undetected by the immune system. This armor also covers other important proteins (ISGs) that the parasites need in order to interact with their host, but must hide to avoid being attacked. However, this protective layer makes it hard for the parasites to reach outside their shield. In our study, we looked at these hidden proteins in detail and discovered that they can change shape. Some can stretch out beyond their protective layer when necessary, while others stay concealed inside. This ability to change shape lets these otherwise hidden proteins interact with their surroundings without getting caught by the immune system. Our findings provide further evidence for a multi-layered defense strategy in these parasites.