Structural basis for the shielding function of the dynamic trypanosome variant surface glycoprotein coat

Abstract

The most prominent defence of the unicellular parasite Trypanosoma brucei against the host immune system is a dense coat that comprises a variant surface glycoprotein (VSG). Despite the importance of the VSG family, no complete structure of a VSG has been reported. Making use of high-resolution structures of individual VSG domains, we employed small-angle X-ray scattering to elucidate the first two complete VSG structures. The resulting models imply that the linker regions confer great flexibility between domains, which suggests that VSGs can adopt two main conformations to respond to obstacles and changes of protein density, while maintaining a protective barrier at all times. Single-molecule diffusion measurements of VSG in supported lipid bilayers substantiate this possibility, as two freely diffusing populations could be detected. This translates into a highly flexible overall topology of the surface VSG coat, which displays both lateral movement in the plane of the membrane and variation in the overall thickness of the coat.

Identification of TOEFAZ1‐interacting proteins reveals key regulators of Trypanosoma brucei cytokinesis

“…The protist parasite Trypanosoma brucei is the causative agent of human African trypanosomiasis (HAT) and nagana in livestock, which are significant medical and economic burdens in Sub-Saharan Africa (Fèvre et al, 2008;Hotez and Kamath, 2009;Simarro et al, 2011;Welburn and Maudlin, 2012). The parasite is an obligate extracellular pathogen that has developed several strategies for avoiding detection and clearance by its hosts (Bartossek et al, 2017;Engstler et al, 2007;Hovel-Miner et al, 2015;Mugnier et al, 2015). Among these adaptations is a highly polarized cell morphology, which is established by a set of microtubules that underlie the cell surface and give the cell body its distinctive tapered shape (Gull, 1999;Vickerman et al, 1979).…”

Evolution of Antigenic Variation in African Trypanosomes: Variant Surface Glycoprotein Expression, Structure, and Function

“…Based on size and disulfide patterns these domains can be sorted into subgroups (NTD, A–C; CTD, 1–4) that have been interchangeably mixed during evolution of the VSG repertoire . The two domains are connected by a flexible linker, and consequently when the first crystal structures were determined only the proteolyzed NTDs were visualized . These were all A‐type NTDs and, despite low sequence identity, they have strikingly similar structures (Figure A).…”

“…The conformation of tightly packed VSGs (left) can elevate the VSG above the transmembrane proteins (dark blue, red), whereas the relaxed conformation (right) could allow the maintenance of a protective coat on the cell surface even at a reduced protein density. Reproduced with permission . Copyright 2017, The Authors.…”

“…Recent developments paint a more nuanced picture. First, the solution structure of several CTDs have been solved by NMR and wedded to corresponding NTDs by small‐angle X‐ray scattering to reveal VSG structure in toto . The results yield a two state model of VSG within the surface coat (Figure B).…”

How to create coats for all seasons: elucidating antigenic variation in African trypanosomes

“…This GPI attachment allows VSGs to move freely over the cell surface [2]. Tight packing of these VSGs produces a protective barrier shielding invariant surface proteins from recognition by host antibodies and preventing trypanosome lysis by the alternative pathway of the complement system [3]. Extraordinarily high rates of recycling of surface VSG allow selective removal of host cell molecules including antibodies and complement from the trypanosome surface, thereby functioning as a 'coat-cleaning ' machine [4].…”