Structural Biology

Introduction

Our interest is to understand the molecular interactions that underlie the cytoplasmic regulation of gene expression, in particular mRNA surveillance (previous/current research) and mRNA localization (future research). We will use both a biochemical and a structural approach to gain insights into the molecular basis and the function of these processes.

Previous Research

After export from the nucleus to the cytoplasm, mRNAs are surveyed for errors that would result in potentially deleterious protein products. One such mechanism is nonsense-mediated mRNA decay (NMD), a pathway that detects and rapidly degrades mRNAs containing premature stop codons. In humans, NMD is dependent on translating cytoplasmic ribosomes and also on the splicing history of the transcript. The link is a complex of proteins, the exon junction complex or EJC. The EJC is deposited onto the mRNA upon splicing, travels with the mRNA to the cytoplasm and here cross-talks with the ribosome (Singh and Lykke-Andersen, 2003). The EJC is formed by the assembly of four core proteins (Y14, Mago, eIF4AIII and Barentsz), all of which are involved in NMD. All EJC components are evolutionarily conserved but influence the fate of the mRNAs differently: all Drosophila melanogaster EJC components are essential for the localized translation of oskar mRNA during embryonic development. We previously solved the structure of the EJC complex and we are now aiming at the structural elucidation of the mechanism by which some of the EJC components are recycled into the nucleus through the association of transport proteins.

Structural studies of mRNA localization protein complexes

mRNA localization plays a crucial role in the development of a wide range of organisms and it is often coupled to translational regulation (St Johnston, 2005). A major question about mRNA localization concerns the molecular interactions that assemble mRNAs into transport particles that often contain multiple mRNA molecules and RNA-binding and regulatory proteins. Although the types of localized transcripts are different in different organisms, the process of mRNA localization shares common features.
Our future plans concern structural aspects of mRNA localization. We would like to study mRNA localization complexes that have been characterized genetically and biochemically in Drosophila melanogaster. The Drosophila melanogaster oocyte is the most extensively studied system for mRNA localization and many components involved in the localization of three different mRNAs (oskar, gurken and bicoid) have been identified. However, the molecular mechanisms of mRNA localization are still elusive. Collaboration with Drosophila melanogaster developmental biologists and cell biologists will also allow us to test the function of specific mutants designed based on the protein structure in vivo and in cell culture.

Scientists involved

Fulvia Bono, Group Leader

Daniela Lazzaretti, Postdoctoral Fellow

Marlene Grünwald, Phd Student

Katharina Veith, Research Technician