Cooperation between a T Domain and a Minimal C-Terminal Docking Domain to 
Enable Specific Assembly in a Multiprotein NRPS

Watzel, Jonas; Duchardt-Ferner, Elke; Sarawi, Sepas; Bode, Helge B.; Wohnert, Jens

doi:10.1002/anie.202103498

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Cooperation between a T Domain and a Minimal C-Terminal Docking Domain to Enable Specific Assembly in a Multiprotein NRPS

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Bode, Helge B.
Natural Product Function and Engineering, Department of Natural Products in Organismic Interactions, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

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Citation

Watzel, J., Duchardt-Ferner, E., Sarawi, S., Bode, H. B., & Wohnert, J. (2021). Cooperation between a T Domain and a Minimal C-Terminal Docking Domain to Enable Specific Assembly in a Multiprotein NRPS. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION. doi:10.1002/anie.202103498.

Cite as: https://hdl.handle.net/21.11116/0000-0008-BDC2-8

Abstract

Non-ribosomal peptide synthetases (NRPS) produce natural products from amino acid building blocks. They often consist of multiple polypeptide chains which assemble in a specific linear order via specialized N- and C-terminal docking domains ((N/C)DDs). Typically, docking domains function independently from other domains in NRPS assembly. Thus, docking domain replacements enable the assembly of "designer" NRPS from proteins that normally do not interact. The multiprotein "peptide-antimicrobial-Xenorhabdus" (PAX) peptide-producing PaxS NRPS is assembled from the three proteins PaxA, PaxB and PaxC. Herein, we show that the small (C)DD of PaxA cooperates with its preceding thiolation (T-1) domain to bind the (DD)-D-N of PaxB with very high affinity, establishing a structural and thermodynamical basis for this unprecedented docking interaction, and we test its functional importance in vivo in a truncated PaxS assembly line. Similar docking interactions are apparently present in other NRPS systems.