Mechanism of intersubunit ketosynthase-dehydratase interaction in polyketide synthases

Jenner, M., Kosol, S., Griffiths, D., Prasongpholchai, P., Manzi, L., Barrow, A. S., Moses, J. E., Oldham, N. J., Lewandowski, J. R., Challis, G. L. (March 2018) Mechanism of intersubunit ketosynthase-dehydratase interaction in polyketide synthases. Nat Chem Biol, 14 (3). pp. 270-275. ISSN 1552-4450 (Print)1552-4450

URL: https://pubmed.ncbi.nlm.nih.gov/29309054/
DOI: 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: Paper
Additional Information: Nature chemical biology
CSHL Authors:
Communities: CSHL labs > Moses lab
Depositing User: Matthew Dunn
Date: March 2018
Date Deposited: 08 Jan 2021 17:27
Last Modified: 08 Jan 2021 17:27
PMCID: PMC5846730
URI: https://repository.cshl.edu/id/eprint/39576

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