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Mechanism of intersubunit ketosynthase–dehydratase interaction in polyketide synthases
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Jenner, Matthew, Kosol, Simone, Griffiths, Daniel, Prasongpholchai, Panward, Manzi, Lucio, Barrow, Andrew S., Moses, John E., Oldham, Neil J., Lewandowski, Józef R. and Challis, Gregory L. (2018) Mechanism of intersubunit ketosynthase–dehydratase interaction in polyketide synthases. Nature Chemical Biology, 14 . pp. 270-275. doi:10.1038/nchembio.2549 ISSN 1552-4450.
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Official URL: https://doi.org/10.1038/nchembio.2549
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.
Item Type: | Journal Article | |||||||||
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | |||||||||
Journal or Publication Title: | Nature Chemical Biology | |||||||||
Publisher: | Nature Publishing Group | |||||||||
ISSN: | 1552-4450 | |||||||||
Official Date: | 1 March 2018 | |||||||||
Dates: |
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Volume: | 14 | |||||||||
Page Range: | pp. 270-275 | |||||||||
DOI: | 10.1038/nchembio.2549 | |||||||||
Status: | Peer Reviewed | |||||||||
Publication Status: | Published | |||||||||
Access rights to Published version: | Restricted or Subscription Access | |||||||||
Date of first compliant deposit: | 15 December 2017 | |||||||||
Date of first compliant Open Access: | 8 July 2018 | |||||||||
Funder: | Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC) | |||||||||
Grant number: | BB/L021692/1 and BB/L022761/1 | |||||||||
RIOXX Funder/Project Grant: |
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