CONICET PhD fellow
Director: Javier Valdez Taubas
PhD Thesis Topic
Structure-function analysis and identification of inhibitors of protein palmitoyl
A family of enzymes known as palmitoyl (PATs) It is responsible for almost all events described palmitoylation. The PATs, are polytopic membrane proteins possessing at least 4 transmembrane segment (TMDs), with a conserved domain 50 amino acids referred DHHC, located between TMDs 2 and 3. Exist 7 Members of this family in the genome Saccharomyces cerevisiae and 23 members in the human genome. Information regarding these proteins is low. From the functional point of view, the S-acylation affects Ras mediated signaling and transforming activity, It is very abundant in synaptic proteins and mutations in PATs they have been associated with mental retardation, schizophrenia and other disorders of the central nervous system. In addition, palmitoylation of proteins some protozoan parasites is essential to the invasion of host cells. For this, There is great interest in achieving specific inhibitors of S-acylation. Within the theme of the laboratory, which involves the study of protein S-acylation, changing mechanism, enzymes involved and the functional consequences thereof, My work plan focuses on two main aspects: 1) Continue studies of structure-function S-acyltransferase Swf1 and complemented by structural and biochemical studies. 2) Through complementation assays in yeast mutants carecientes different PATs, PAT-substrate pairs identified in the parasite Giardia lamblia. Later, generate tests in yeast to isolate specific inhibitors of parasite PATs expressed heterologously.
PhD Thesis Topic
Structure-function analysis and identification of inhibitors of protein palmitoyltransferases
Protein S-acylation commonly known as palmitoylation, is a posttranslational modification that consists in the addition of long-chain lipids on cysteine residues through a thioesther bond. This modification participates in the regulation of several processes of biological importance such as signal transduction and synaptic plasticity. A family of enzymes named Palmitoyltransferases (PATs) is responsible of almost all events of palmitoylation that have been described. PATs are polytopic membrane proteins characterized by the presence of a conserved 50 amino acid -long DHHC cysteine rich domain. There are 7 members of this family in Saccharomyces cerevisiae and 23 in humans. The information regarding these enzymes is still very scarce. Our Lab, focuses on Swf1 a PAT from S. cerevisiae involved in the S-acylation of type II transmembrane proteins, such as SNAREs and glycosyltransferases. There is growing interest in the identification of inhibitors of S-acylation, due to its role in host-cells invasion by some parasites. Additionally, PATs are involved in different types of cancers. The focus of my PhD thesis will be: 1) To continue structure-function analyses of the PAT Swf1 and complement them with structural and biochemical studies. 2) To generate assays in yeast that will enable me to isolate specific inhibitors for PATs.