Structural basis of protein sorting and targeting in the secretory pathway.

Cells have elaborate internal compartments and specialized proteins that function inside or outside the plasma membrane. A remarkably selective process that contributes to cell organization and protein trafficking is the Sec secretion pathway. This essential and ubiquitous export machinery comprises several specific components: molecular chaperones like SecA and SecB sort and target pre-proteins to the membrane; SecYEG forms membrane-embedded pores and exports non-folded proteins through them. The polypeptides translocating through the Sec are synthesized as pre-proteins, carrying signal peptides 20-30 residue long, that are cleaved off during or after translocation and only then the mature-proteins can fold and reach their destinations. This highly interdisciplinary project proposes an in depth analysis of the molecular and structural basis of the post-translational secretion process. The goal is to describe how the exported proteins are recognized by SecA and SecB, what the complexes look like structurally and how the process of pre-protein delivery works. To answer these fundamental questions I aim to provide high-resolution 3D snap-shots of the assemblies and their interaction networks with advanced biochemical, biophysical and structural techniques. These advances will facilitate the development of novel antibiotics and the production of biopharmaceuticals in bacterial cell factories.