The human and animal trypanosomiases have medical, veterinary, social, economic and nutritional consequences throughout equatorial Africa. The salivarian trypanosomes have developed a unique mechanism for antigenic variation, which enables them to avoid elimination by the host's immune responses. Each trypanosome is covered by a surface coat consisting of a closely packed layer of about 10 million molecules of, essentially single molecular species of a large family of variant surface glycoproteins (VSGs). Antigenic variation occurs by gene rearrangements which regulate the sequential expression of 100-1,000 individuals genes encoding antigenically distinct VSGs. Comparison of nucleotide sequences of cloned VSG genes with amino acid sequences of purified VSGs implied the existence of a precursor containing hydrophobic leader and tail sequences not found on conventional purified VSGs, soluble molecules rapidly released from disrupted trypanosomes in the absence of detergents. The metastability of the VSG coat was an enigma until recently when it became clear that membrane-attached VSG (mfVSG) contains a hydrophobic moiety which is removed concomitantly with the release of soluble VSG (sVSG), during cell disruption. Preliminary studies indicated the presence of a C-terminal uniquely-linked glycophospholipid-liked moiety which is substituted for the C-terminal hydrophobic peptide present on the primary translation product. The processing of a C-terminal peptide, the attachment of a novel lipophilic moiety as a membrane anchor and the presence of an enzymatic mechanism for release of a membrane-attached glycoprotein, are features unique to trypanosome VSGs.
The aims of this proposal are to determine the chemical structure of the C-terminal lipophilic anchor, to study the biosynthetic pahtways involved in this unique sequence of post-translational glycoprotein modifications and to investigate the enzymic activity responssible for VSG release. This research will open up new possibilities for consideration as potential targets for therapeutic intervention.
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