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      Selective Protein−Protein Interactions Direct Channeling of Intermediates between Polyketide Synthase Modules†

      , ,
      Biochemistry
      American Chemical Society (ACS)

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          Abstract

          Polyketide synthases (PKSs) have represented fertile targets for rational manipulation via protein engineering ever since their modular architecture was first recognized. However, the mechanistic principles by which biosynthetic intermediates are sequentially channeled between modules remain poorly understood. Here we demonstrate the importance of complementarity in a remarkably simple, repetitive structural motif within these megasynthases that has been implicated to affect intermodular chain transfer [Gokhale, R. S., et al. (1999) Science 284, 482]. The C- and N-terminal ends of adjacent PKS polypeptides are capped by short peptides of 20-40 residues. Mismatched sequences abolish intermodular chain transfer without affecting the activity of individual modules, whereas matched sequences can facilitate the channeling of intermediates between ordinarily nonconsecutive modules. Thus, in addition to substrate-PKS interactions and domain-domain interactions, these short interpolypeptide sequences represent a third determinant of selective chain transfer that must be taken into consideration in the protein engineering of PKSs. Preliminary biophysical studies on synthetic peptide mimics of these linkers suggest that they may adopt coiled-coil conformations.

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          Author and article information

          Journal
          Biochemistry
          Biochemistry
          American Chemical Society (ACS)
          0006-2960
          1520-4995
          February 2001
          February 2001
          : 40
          : 8
          : 2326-2331
          Article
          10.1021/bi002463n
          11327852
          47a7cb85-cbf2-41c4-b55e-a642dd3ccf86
          © 2001
          History

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