The 70 kDa Heat shock proteins (Hsp70s), also known as molecular chaperones, have evolved to function in specialized biological processes, in addition to the general role in protein folding. For example, the major mitochondrial Hsp70 (mtHsp70) plays a central role in protein import across the mitochondrial inner membrane. Since the vast majority of mitochondrial proteins are synthesized on cytosolic ribosomes, efficient protein translocation is critical for mitochondrial biogenesis, as indicated by the essential nature of components of the translocase of the inner membrane (TIM) and the mtHsp70 based """"""""import motor"""""""". Tim44, a peripheral membrane component of the TIM complex, is believed to serve as a tether for mtHsp70 to the import channel and release it from the translocase upon binding a substrate protein, the translocating polypeptide. However, little is understood about the mtHsp70:Tim44 interaction and the mechanism behind the destabilization of the mtHsp70:Tim44 complex upon peptide binding. The goal of this proposal is to better understand the interaction between chaperone components of the """"""""import motor"""""""" and the TIM complex and their importance in the translocation process. Using Saccharomyces cerevisiae as a model system, I aim to dissect the mtHsp70:Tim44 interaction and test the importance for the dynamic nature of this interaction on protein translocation. The results of my experiments will provide insight into this important biological process, as well as serve as an example of how Hsp70s have evolved specific regulated protein:protein interaction that allow them to function in specialized biological processes while utilizing their fundamental biochemical property: interaction with short hydrophobic segments of amino acids. Recent genomic data suggested that the regulation of expression of import motor components may be involved in heart hypertrophy treatments and diabetes. Moreover, mitochondria, whose biogenesis depends upon protein translocation of hundreds of proteins translated in the cytosol, are involved, in part, in numerous diseases (e.g. neurological disorders, cancer, and metabolic diseases), as well as the aging processes, indicating that the basic cell biological problems converge on the issues of public health. ? ? ?
| Gerrish, Philip J; Colato, Alexandre; Sniegowski, Paul D (2013) Genomic mutation rates that neutralize adaptive evolution and natural selection. J R Soc Interface 10:20130329 |
| Sprouffske, Kathleen; Merlo, Lauren M F; Gerrish, Philip J et al. (2012) Cancer in light of experimental evolution. Curr Biol 22:R762-71 |
| Gerrish, Philip J; Sniegowski, Paul D (2012) Real time forecasting of near-future evolution. J R Soc Interface 9:2268-78 |
| de la Iglesia, Francisca; Martinez, Fernando; Hillung, Julia et al. (2012) Luria-delbruck estimation of turnip mosaic virus mutation rate in vivo. J Virol 86:3386-8 |
