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Cooperation between a T Domain and a Minimal C‐Terminal Docking Domain to Enable Specific Assembly in a Multiprotein NRPS
Author(s) -
Watzel Jonas,
DuchardtFerner Elke,
Sarawi Sepas,
Bode Helge B.,
Wöhnert Jens
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202103498
Subject(s) - docking (animal) , peptide , stereochemistry , computational biology , biology , biochemistry , chemistry , medicine , nursing
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 N DD 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.