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
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 |
| Subjects: | bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics organism description > bacteria bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations > mutagenesis bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations |
| CSHL Authors: | |
| Communities: | CSHL labs > Moses lab |
| Depositing User: | Matthew Dunn |
| Date: | March 2018 |
| Date Deposited: | 08 Jan 2021 17:27 |
| Last Modified: | 20 Feb 2024 21:00 |
| PMCID: | PMC5846730 |
| URI: | https://repository.cshl.edu/id/eprint/39576 |
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