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Publication Detail

Title: Probing the selectivity and protein·protein interactions of a nonreducing fungal polyketide synthase using mechanism-based crosslinkers.

Authors: Bruegger, Joel; Haushalter, Robert W; Haushalter, Bob; Vagstad, Anna L; Vagstad, Anna; Shakya, Gaurav; Mih, Nathan; Townsend, Craig A; Burkart, Michael D; Tsai, Shiou-Chuan

Published In Chem Biol, (2013 Sep 19)

Abstract: Protein·protein interactions, which often involve interactions among an acyl carrier protein (ACP) and ACP partner enzymes, are important for coordinating polyketide biosynthesis. However, the nature of such interactions is not well understood, especially in the fungal nonreducing polyketide synthases (NR-PKSs) that biosynthesize toxic and pharmaceutically important polyketides. Here, we employ mechanism-based crosslinkers to successfully probe ACP and ketosynthase (KS) domain interactions in NR-PKSs. We found that crosslinking efficiency is closely correlated with the strength of ACP·KS interactions and that KS demonstrates strong starter unit selectivity. We further identified positively charged surface residues by KS mutagenesis, which mediates key interactions with the negatively charged ACP surface. Such complementary/matching contact pairs can serve as "adapter surfaces" for future efforts to generate new polyketides using NR-PKSs.

PubMed ID: 23993461 Exiting the NIEHS site

MeSH Terms: Acyl Carrier Protein/chemistry; Acyl Carrier Protein/metabolism; Amino Acid Sequence; Cross-Linking Reagents/chemistry; Electrophoresis, Polyacrylamide Gel; Molecular Sequence Data; Mutagenesis; Pantetheine/chemistry; Polyketide Synthases/chemistry; Polyketide Synthases/genetics; Polyketide Synthases/metabolism*; Polyketides/chemistry; Polyketides/metabolism; Protein Interaction Domains and Motifs; Recombinant Proteins/biosynthesis; Recombinant Proteins/chemistry; Recombinant Proteins/genetics; Sequence Alignment

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