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Edited by Mohamed A. Marahiel, Philipps-Universität Marburg, Marburg, Germany, and accepted by Editorial Board Member Michael A. Marletta December 27, 2018 (received for review July 5, 2018)
Significance
Nonribosomal peptide synthesis is responsible for the formation of many important peptide natural products in bacteria and fungi; it typically utilizes a modular architecture of repeating catalytic domains to produce these diverse peptide structures. The protein Ebony from Drosophila melanogaster is a rare example of such a nonribosomal peptide synthetase from a higher eukaryote, where it plays a central role in the regulation of amine neurotransmitters. Here, we reveal that the C-terminal portion of Ebony encodes an atypical peptide bond-forming nonribosomal peptide synthesis domain. Structural analysis shows that this domain adopts a fold not predicted by its primary sequence, and indicates how this domain maintains its high degree of substrate specificity.
Abstract
The protein Ebony from Drosophila melanogaster plays a central role in the regulation of histamine and dopamine in various tissues through condensation of these amines with β-alanine. Ebony is a rare example of a nonribosomal peptide synthetase (NRPS) from a higher eukaryote and contains a C-terminal sequence that does not correspond to any previously characterized NRPS domain. We have structurally characterized this C-terminal domain and have discovered that it adopts the aryl-alkylamine-N-acetyl transferase (AANAT) fold, which is unprecedented in NRPS biology. Through analysis of ligand-bound structures, activity assays, and binding measurements, we have determined how this atypical condensation domain is able to provide selectivity for both the carrier protein-bound amino acid and the amine substrates, a situation that remains unclear for standard condensation domains identified to date from NRPS assembly lines. These results demonstrate that the C terminus of Ebony encodes a eukaryotic example of an alternative type of NRPS condensation domain; they also illustrate how the catalytic components of such assembly lines are significantly more diverse than a minimal set of conserved functional domains.
- nonribosomal peptide synthetase
- NRPS
- condensation reaction
- C domain
- aryl-alkylamine N-acetyl transferase
Footnotes
- ↵1To whom correspondence may be addressed: Email: thierry.izore{at}monash.edu or max.cryle{at}monash.edu.
Author contributions: T.I., J.T., and M.J.C. designed research; T.I., J.T., M.H.H., and J.A.K. performed research; T.I., J.T., J.A.K., C.J.J., and M.J.C. analyzed data; and T.I. and M.J.C. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. M.A.M. is a guest editor invited by the Editorial Board.
Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.wwpdb.org (PDB ID codes 6DYM, 6DYN, 6DYO, 6DYR, and 6DYS).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1811194116/-/DCSupplemental.
Published under the PNAS license.
Drosophila melanogaster nonribosomal peptide synthetase Ebony encodes an atypical condensation domain
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- Biochemistry
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