A structural motif in the variant surface glycoproteins of Trypanosoma brucei

Abstract

The variable domain of the trypanosome variant surface glycoprotein (VSG) ILTat 1.24 has been shown by X-ray crystallography to resemble closely the structures of VSG MITat 1.2, despite their low sequence similarity. Specific structural features of these VSGs, including substitution of carbohydrate for an alpha-helix, can be found in other VSG sequences. Thus antigenic variation in trypanosomes is accomplished by sequence variation, not gross structural alteration; the extensive sequence differences among VSGs may be required for another reason, such as the avoidance of recognition by helper T cells. Additionally, VSG sequences are found to define families, within a VSG superfamily, which have evolved in the trypanosome genome.

Sequence variation and structural conservation allows development of novel function and immune evasion in parasite surface protein families

“…Structural studies of the trypanosome VSGs led to the conclusion that “the African trypanosomal antigens accomplish antigenic variation through the variation of sequence and limited conformational modification and not by gross alteration of structure.”11 More recent studies have shown further diversification of this basic fold to allow the development of ligand binding in proteins that bind nutrients or innate immune factors. Furthermore, a more simple monomeric, and probably ancestral, three‐helical bundle architecture is found in receptors such as that for haptoglobin‐haemoglobin.…”

“…Structural studies, conducted some 20 years ago, demonstrated that, despite a high degree of sequence diversification, VSGs share a common fold 11. More recent studies have shown that this fold, and the related three‐helical bundle architecture, can diversify further, generating ligand‐binding functions essential for trypanosome survival and human infectivity 12…”

“…1(A)]. These conserved residues are predominantly buried and are important in determining the protein fold 11. They include heptad repeats with hydrophobic faces that seal together the α‐helices of the hairpin, glycine, or proline residues at the kinks in these α‐helices and a conserved glycine that allows the two monomers to approach closely at the dimer interface.…”

Antigenic diversity is generated by distinct evolutionary mechanisms in African trypanosome species

“…To survive long-term, T. brucei must generate novel VSG sequences through recombination; mechanisms may include domain shuffling (7) and gene conversion among silent, subtelomeric gene copies or possibly in situ within the expression site (8). Functional variant antigens in T. brucei consist of a-and b-type VSG (hereafter a-VSG and b-VSG), which share the cysteine-rich C-terminal domain (CTD) but are otherwise distantly related (9)(10)(11). Although VSG are known to occur in T. congolense and T. vivax (12)(13)(14)(15)(16), the repertoire of variant antigens in these species is uncharacterized.…”

Biological Variation Among African Trypanosomes: I. Clonal Expression of Virulence Is Not Linked to the Variant Surface Glycoprotein or the Variant Surface Glycoprotein Gene Telomeric Expression Site

“…Based on earlier partial amino acid sequence analyses of the VSG proteins from LouTat 1 and 1A (Inverso et al, 1988), we predict that the precursor molecule is processed to a mature VSG of 461 amino acids, beginning at the N-terminus with threonine 27 and ending with conserved residues common to type I VSG molecules at the C-terminus. The LouTat 1=1A VSG molecule also contains conserved residues throughout the molecule, which are common to VSGs as a family (Rice-Ficht et al, 1981;Reinitz et al, 1992;Blum et al, 1993).…”