Interdisciplinary Initiatives Program Round 12 - 2024
Project Investigators:
Laura Dassama, Chemistry and Microbiology & Immunology
Matthias Garten, Microbiology & Immunology and Bioengineering
Abstract:
The malaria parasite Plasmodium falciparum is known to acquire and use host lipids as it proliferates, and in doing so, alter host lipid metabolism. Drugs that target de novo lipid synthesis and acquisition pathways could introduce a new therapeutic modality. However, few proteins that mediate the transfer of lipids from host to parasite have been identified. Functional disruption of a lipid acquisition protein resulted in reduced proliferation and increased sensitivity to existing antimalaria drugs, suggesting that similar machineries can be targeted for malaria drug development. One challenge in identify lipid binding proteins using traditional sequence-based approaches is the poor conservation of amino acids at lipid binding sites preventing the assignment of binding motifs. To overcome this challenge, we recently developed SLiPP, a structural bioinformatics algorithm that detects in a sequence unbiased manner protein cavities amenable to lipid binding. Application of SLiPP to the P. falciparum proteome revealed proteins annotated as being involved in lipid related processes but also many other uncharacterized proteins. In this proposal, we will employ a multidisciplinary strategy using bioinformatics, protein biochemistry, and genetic manipulation of the parasite to assess the relevance of these proteins to cell proliferation and pathogenesis. We posit that the outcome of this project is the identification of several novel lipid transfer proteins that can be targeted for treatment of malaria. Moreover, the project will establish a pipeline for the identification and characterization of lipid binding proteins in non-model organisms.
