Untersuchung der Wechselwirkung von PCP Domänen mit Interaktionspartnern in Nicht-ribosomalen Peptidsynthetasen

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Non-ribosomal peptide synthetases (NRPS) constitute a class of large multidomain enzymes found in the cytoplasm of bacteria and fungi that produce a large set of peptides with biological activities ranging from iron sequestration to chemical defense against other microbes. Many of these peptides are used as drugs with antibiotic, anticancer or immunosuppressive activity, making NRPS systems of high medical importance. The modular structure of these NRPS systems has fueled attempts to create new, potentially medically important peptides by combining modules from different NRPS systems into new assembly lines. However, many design experiments have shown that even small changes in the assembly lines result in significant reductions in yield, suggesting that the individual modules are not mere beads on a string but that specific domaindomain interactions play important roles. In previous studies we investigated the interaction of peptide carrier proteins (PCPs) with thioesterases and other intrans interacting enzymes. In this grant application we describe detailed studies of the domain-domain interaction of PCPs with the major components of NRPS systems, the A- and the C-domains that are responsible for amino acids type selection and for performing the chemical condensation step of the reaction. In particular we will focus on the role of peptides that are covalently attached to the PCP and that modulate the interaction with C-domains.