Characterization of protein complexes and protein interaction networks is a key proteomic strategy for developing functional insights into cellular pathways. Two widely used methods for protein interaction discovery are yeast two-hybrid screening and analysis of protein complexes by mass spectrometry. We have applied these technologies to studying molecular aspects of two different human diseases. In HD, a mutation in the huntingtin protein leads to expression of an expanded polyglutamine tract. The normal function of huntingtin is not known. Mutant huntingtin causes neuronal dysfunction and death through a mechanism that is poorly understood. Through a combination of Y2H screening against multiple tissue libraries, and MS studies of protein complexes derived from different cell and tissue sources, we have identified more than 100 novel huntingtin interacting proteins. Functional annotations of these proteins, and the properties of interaction networks they participate in, are consistent with known clinical features of HD. The networks also implicate novel pathways for tissue specific pathogenic mechanisms. Our malaria studies have focused on developing a comprehensive protein interaction map of the malarial parasite Plasmodium falciparum. Using Y2H, we have identified more than 5,000 unique pair-wise interactions between Plasmodium proteins. We have also initiated studies to discover interspecific interactions between P. falciparum and human proteins. Such interactions may play a role in parasite to infection and survival in the host. A summary of these results will be presented.
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