Structure-function studies of the human FASTK family of mitochondrial proteins with putative novel RNA binding domains – the helical FAST motifs and the small RAP domain

ended

The purpose of this project is three-fold. The main aim is to elucidate the structure of two novel RNA binding folds: the helical FAST motifs and the small RAP domain that are predicted in the Fas-activated Serine/Threonine Kinase (FASTK) protein family. To this purpose, I will employ protein crystallography and small angle X-ray scattering to obtain models of FASTK proteins and their domains. The second objective is to understand the function of the FASTK family of mitochondrial RNA-binding proteins that were originally annotated as atypical kinases. The eponymous FASTK engages in processes similar to its interaction partner, the post-transcriptional regulator TIA-1, whereas some of the other five human paralogs are necessary for cellular respiration. I will use purified FASTK proteins to study their enzymatic activities and RNA-binding properties in vitro, which should clarify their functional classification as kinases or post-transcriptional regulators. Additionally, follow-up studies may include validation of the findings through informed mutagenesis, identification of RNA targets, protein partners, and selected phenotypes in RNA biology. The final goal of this project is to enable a young researcher to establish herself as an independent researcher, creating a group which will focus on mitochondrial RNA-binding proteins and employ X-ray crystallography as the main tool. Altogether, this interdisciplinary project will 1) Impact various fields of research, such as structural and RNA biology 2) Has the potential for applications in human health due to the connections of the FASTK family to mitochondrial and inflammatory diseases, 3) Significantly develop the career of a talented researcher and 4) Contribute to the academic and research excellence at the University of Warsaw by establishing a new research group, introducing structural biology expertise, and bringing together local and international collaborations.