This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.This collaboration has been a broadly based examination of tyrosine sulfation,a widespread posttranslational modification of proteins and peptide hormonesthat pass through the Golgi system of animal cells. When the project began itwas limited to a number of the peptide hormones involved in the digestiveprocess and some, for example Cholecystokinin (CCK), active both in thegastrointestinal tract and in the central nervous system. The two tissuesexpress different but closely related receptors. The tyrosine sulfationposttranslational modification has been estimated to occur to about one percentof tyrosine residues in Rat proteins. Our initial papers focused on findingand testing rules that could be used to accurately predict tyrosine sulfationsites (1,2,3). These initial studies led to the conclusions thattyrosylprotein sulfotransferase, the enzyme that catalyzes the sulfation oftyrosine residues in proteins and peptides, has a relatively low substratespecificity and is likely to modify any tyrosine residue that is sufficientlyexposed and is near negatively charged side chains.Recently it has been discovered that tyrosine sulfation of specific cytokinereceptors molecules is an essential requirement for some modes of infection ofthe HIV-1 virus and increases the efficiency of other modes of infection (5). Additionally, tyrosine sulfation has been shown to be required for the activityof some subfamilies within the glycoprotein hormone receptors family and seemsto play a similar role in other subfamilies (6). Thus we have been exploringthe possibility that other receptor families may require tyrosine sulfation foreither effective or full activity. We have been correlating our predictions oftyrosine sulfation binding sites with additional biochemical information aboutthe location of receptor binding site within the protein chain. We predict that 49 tyrosines of 32 seven-transmembrane peptide receptors aresulfated. Although we did not incorporate characteristics of confirmedsulfation sites such as clustering and conservation across species into ourprofile (Position Specific Scoring Matrix, PSSM), our predicted sitesnevertheless exhibited these characteristics. The observed conservationsuggests that there are strong evolutionary pressures to preserve selectedbiological activity of seven-transmembrane peptide receptors. The predictedtyrosine sulfation sites predominantly occur in the extracellular tail andextracellular loop 2, regions consistent with their association with bindingpockets of the receptor (4).Post-translational modification of proteins by tyrosine sulfation enhances theaffinity of extracellular ligand-receptor interactions important in the immune
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