Mechanism of intersubunit ketosynthase-dehydratase interaction in polyketide synthases

Nat Chem Biol. 2018 Mar;14(3):270-275. doi: 10.1038/nchembio.2549. Epub 2018 Jan 8.


Modular polyketide synthases (PKSs) produce numerous structurally complex natural products that have diverse applications in medicine and agriculture. PKSs typically consist of several multienzyme subunits that utilize structurally defined docking domains (DDs) at their N and C termini to ensure correct assembly into functional multiprotein complexes. Here we report a fundamentally different mechanism for subunit assembly in trans-acyltransferase (trans-AT) modular PKSs at the junction between ketosynthase (KS) and dehydratase (DH) domains. This mechanism involves direct interaction of a largely unstructured docking domain (DD) at the C terminus of the KS with the surface of the downstream DH. Acyl transfer assays and mechanism-based crosslinking established that the DD is required for the KS to communicate with the acyl carrier protein appended to the DH. Two distinct regions for binding of the DD to the DH were identified using NMR spectroscopy, carbene footprinting, and mutagenesis, providing a foundation for future elucidation of the molecular basis for interaction specificity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl Carrier Protein / chemistry
  • Acyltransferases / chemistry
  • Bacteria / enzymology
  • Cross-Linking Reagents / chemistry
  • Hydro-Lyases / chemistry
  • Lyases / chemistry*
  • Magnetic Resonance Spectroscopy
  • Markov Chains
  • Methane / analogs & derivatives
  • Methane / chemistry
  • Mutagenesis
  • Phylogeny
  • Polyketide Synthases / chemistry*
  • Protein Binding*
  • Protein Domains
  • Protein Structure, Secondary


  • Acyl Carrier Protein
  • Cross-Linking Reagents
  • carbene
  • Polyketide Synthases
  • Acyltransferases
  • Lyases
  • Hydro-Lyases
  • Methane