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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.