A structure-function analysis of mortalin- toward developing new cancer therapies


 Dr. Abdussalam Azem



The mitochondrial 70 kDa heat shock protein (mtHsp70; in mammals named mortalin) plays a key role in the biogenesis of mitochondrial proteins [1-3]. Studies carried during the last decade have provided strong evidence that mortalin is involved in additional, essential, extra-mitochondrial pathways [4]. Relevant to this proposal is the involvement of mortalin in carcinogenesis. In this context, it is known that mortalin is overexpressed, and displays altered subcellular localization, in tumor cells. These phenomena correlate with increased malignancy in many cancer cells [5-7].

Mortalin is able to perform several disparate functions due to its ability to interact with many distinct proteins in several cellular compartments. For example, mortalin performs its folding activity within mitochondria with the help of two co-chaperone proteins, Mge1 and Mdj1 (names of yeast proteins). In the cytosol, it was shown that mortalin interacts with P53 thereby causing its sequestration in the cytoplasm. Other examples of cytosolic interactions have been reported [4].

The specific goals of this study are as follows:

 i) To carry out an in vitro structure-function analysis of complexes between mortalin and a selected number of its previously reported partner proteins. ii) To identify new cellular proteins that may interact with mortalin in normal and tumor cells. iii) To identify new compounds that will be able to inhibit the function of mortalin.

 We anticipate that the results of this project will increase our understanding of the molecular basis for the involvement of mortalin in development of cancer and will facilitate the discovery of mortalin inhibitors with potential to serve as a basis for new cancer therapies.