The African trypanosome Trypanosoma brucei has a precarious existence as an extracellular parasite of the mammalian bloodstream, where it is faced with continuous immune attack. Key to survival is a dense VSG (variant surface glycoprotein) coat, which is repeatedly switched during the course of a chronic infection. New data demonstrate a link between VSG synthesis and cell cycle progression, indicating that VSG is monitored during the trypanosome cell cycle. The structure of the protective VSG (variant surface glycoprotein) coat Bloodstream form Trypanosoma brucei is coated with a densely packed layer of VSG, which is attached to the surface membrane via a GPI (glycosylphosphatidylinositol) anchor. An intact VSG coat protects the trypanosome from lysis by the alternative pathway of the complement system [1,2]. However, VSGs are highly antigenic, and eventually the trypanosome succumbs to antibody-mediated lysis. The parasite therefore relies on its ability to switch betweenthemutuallyexclusiveexpressionofoneofhundreds of immunologically distinct VSGs to maintain a chronic infection [3]. VSGs have a highly conserved tertiary structure with an extremely diverse N-terminal ‘variable’ domain containing two long antiparallel α-helices separated by a turn [4]. Insertion of epitope tags into various regions of VSG can result in drastic reductions in expression level, indicating stringent quality controls on these molecules before they reach the parasite surface [5]. A striking feature of VSGs is that regions of the molecule which are highly divergent (only 16% conservation in amino acid sequence), can nonetheless have very similar tertiary structures [4,6]. The VSG gene family therefore appears to have evolved through a ‘tug of war’ between two evolutionary selection pressures: one for antigenic diversity resulting in sequence divergence, and another for conservation of tertiary structure, which presumably facilitates packing of different VSGs within the coat of a switching trypanosome [7]. The VSG layer shields invariant proteins on the cell surface from recognition by antibodies. The VSG-fold (a conserved tertiary structure characteristic of VSG) can also be found in a variety of invariant surface molecules, presumably allowing a nondisruptive fit into the protective VSG layer [7–9].
