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J Biol Chem. 2017 Jun 16;292(24):10002-10013. doi: 10.1074/jbc.M116.766220. Epub 2017 Apr 28.

Molecular impact of covalent modifications on nonribosomal peptide synthetase carrier protein communication.

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From the Department of Biophysics and Biophysical Chemistry and.
the Department of Pharmacology and Molecular Sciences Synthetic Core Facility, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
From the Department of Biophysics and Biophysical Chemistry and


Nonribosomal peptide synthesis involves the interplay between covalent protein modifications, conformational fluctuations, catalysis, and transient protein-protein interactions. Delineating the mechanisms involved in orchestrating these various processes will deepen our understanding of domain-domain communication in nonribosomal peptide synthetases (NRPSs) and lay the groundwork for the rational reengineering of NRPSs by swapping domains handling different substrates to generate novel natural products. Although many structural and biochemical studies of NRPSs exist, few studies have focused on the energetics and dynamics governing the interactions in these systems. Here, we present detailed binding studies of an adenylation domain and its partner carrier protein in apo-, holo-, and substrate-loaded forms. Results from fluorescence anisotropy, isothermal titration calorimetry, and NMR titrations indicated that covalent modifications to a carrier protein modulate domain communication, suggesting that chemical modifications to carrier proteins during NRPS synthesis may impart directionality to sequential NRPS domain interactions. Comparison of the structure and dynamics of an apo-aryl carrier protein with those of its modified forms revealed structural fluctuations induced by post-translational modifications and mediated by modulations of protein dynamics. The results provide a comprehensive molecular description of a carrier protein throughout its life cycle and demonstrate how a network of dynamic residues can propagate the molecular impact of chemical modifications throughout a protein and influence its affinity toward partner domains.


adenylation domain; allostery; antibiotics; aryl carrier protein; nonribosomal peptide synthetase; nuclear magnetic resonance (NMR); protein dynamic; protein-protein interaction; structural biology

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