Mechanism of intersubunit ketosynthase-dehydratase interaction in polyketide synthases

Matthew Jenner, Simone Kosol, Daniel Griffiths, Panward Prasongpholchai, Lucio Manzi, Andrew Barrow, John Moses, Neil Oldham, Józef Lewandowski, Gregory L Challis

Research output: Contribution to journalArticleResearchpeer-review

13 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)270-275
Number of pages6
JournalNature Chemical Biology
Volume14
Issue number3
DOIs
Publication statusPublished - 1 Mar 2018
Externally publishedYes

Cite this

Jenner, M., Kosol, S., Griffiths, D., Prasongpholchai, P., Manzi, L., Barrow, A., Moses, J., Oldham, N., Lewandowski, J., & Challis, G. L. (2018). Mechanism of intersubunit ketosynthase-dehydratase interaction in polyketide synthases. Nature Chemical Biology, 14(3), 270-275. https://doi.org/10.1038/nchembio.2549