African trypanosomes are parasitic protozoa which are responsible for human and animal diseases. These parasites live in the host's bloodstream, and they escape the immune system by undergoing antigenic variation. Antigenic variation is mediated by a glycoprotein known as the Variant Surface Glycoprotein (VSG). This protein forms a dense surface coat which covers the entire cell. During antigenic variation the parasite synthesizes a new VSG, with a different amino acid sequence, and therefore exchanges its old coat for a new one. Each parasite has genetic potential to synthesize more than 100 different VSGs. The objective of this proposal is to study the biosynthesis, structure, and turnover of VSG. Emphasis will be directed towards the structure and synthesis of the moiety at the VSG C-terminus which contains carbohydrate, phosphate, ethanolamine, and probably lipid. This putative lipid presumably serves to anchor the VSG to the cell's plasma membrane.
Specific aims i nclude: 1) A study of the temporal sequence of processing events at the VSG C-terminus. Processing includes removal of a peptide sequence and attachment of sugars, phosphate, ethanolamine, and lipid. 2) A structural determination of the moiety at the C-terminus. 3) A search for an enzyme that cleaves the lipid from the VSG and therefore releases these molecules from the cell. This enzyme may be involved in the exchange of surface coats during antigenic variation, and it may be highly regulated so as not to release the surface coat at inappropriate times. These studies may lead to the discovery of biochemical structures and pathways which are unique to trypanosomes. This knowledge may lead to new modes of chemotherapy against these parasites.
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