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Glycosomes are subcellular organelles that are evolutionarily related to the peroxisomes of higher eukaryotes. The Leishmania glycosome performs various metabolic processes that are essential for the survival of these parasites, such as the glycolytic process. Proteins that are destined for import into the glycosome interact selectively with specific cytosolic receptors peroxin 5(PEX5) or PEX7. The PEX5-protein complex migrates toward the glycosomal membrane where it interacts with PEX14, a vital step for protein important into the glycosome. / This project investigated the interaction mechanism of Leishmania donovani PEX14 with the glycosomal membrane. The regions responsible for PEX14 interaction with the glycosomal membrane are established in higher eukaryotes. LdPEX14 is poorly conserved with respect to the other PEX14 homologues. In Leishmania the interaction of LdPEX14 with the glycsomal membrane has been shown to be unique in terms of its lack of insertion in the glycosomal membrane. Using LdPEX14 mutants it was determined that the first 63 amino acids are important for the interaction of LdPEX14 with the glycosomal membrane. Results further suggest that LdPEX14 is a homopolymer forming a complex of 20S in size which is vital for the proper functioning of the glycosome.

[Truncated abstract] Neuregulins (NRG’s) are pleiotropic growth factors that participate in a wide range of biological processes. The family of membrane-bound growth factors bind to and activate ErbB receptors on adjacent target cells, mediating multiple biological processes. NRG-1, NRG-2 and NRG-3 are all highly expressed in the nervous system, where it has been shown that NRG-1 is important for neuronal development, migration, synapse formation and glial cell proliferation. Little is known, however, on the specific roles of NRG-2 and NRG-3, although it is apparent that despite similar expression patterns and overlapping receptor specificity, NRG-2 and NRG-3 do not compensate for the loss of NRG-1 and mediate their own distinct activities. … Subcellular localisation experiments showed that this domain is important for trafficking of the fulllength protein to various intracellular compartments in an activity dependent manner. In addition, the ICD is required to elicit a cell death response in cultured cells and provoke an elevated α-amino-3-hydroxyl-5-methylisoxazole-4-propionate (AMPA) response in organotypic neuronal cultures following transient expression of NRG-3. A yeast two-hybrid screen identified 14-3-3ζ and PICK1 as two proteins that interacte with the human NRG-3 ICD. These interactions were confirmed both in vitro and in vivo, and were further characterised at a molecular level. This study demonstrates the ability of NRG-3 to mediate signal transduction through a biologically active ICD; a conclusion supported by identifying cytoplasmic proteins that interact with the ICD. These observations point to an additional layer of complexity where bi-directional signalling contributes to the full repertoire of NRG-3 functions.

Thesis (Ph.D.). / Written for the Institute of parasitology. Title from title page of PDF (viewed 2009/06/10). Includes bibliographical references.