The Structure of Docking Domains in Modular Polyketide Synthases (original) (raw)

2003, Chemistry & Biology

that house extender modules (i.e., the regions N-terminal of the KS domain) contain regularities in their University of Cambridge 80 Tennis Court Road amino acid sequence typical of amphipathic parallel ␣-helical coiled coils [10], led to the proposal that these Cambridge CB2 1GA United Kingdom N termini are involved in specific coiled-coil interactions that stabilize PKS homodimeric assemblies . More recent studies have highlighted the potential role of these regions as "linkers" interacting with partner Summary "linker" regions at the extreme C termini of the previous PKS multienzyme. These linker regions are referred to Polyketides from actinomycete bacteria provide the here as "docking domains," given that they adopt a basis for many valuable medicines, so engineering specific three-dimensional fold, as discussed below. genes for their biosynthesis to produce variant mole-Khosla and colleagues have reported that docking docules holds promise for drug discovery. The modular main partners can be substituted by other such partners polyketide synthases are particularly amenable to this without impairing biological function of the PKS [12, approach, because each cycle of chain extension is 13], and that they can also mediate acyl chain transfer catalyzed by a different module of enzymes, and the between some domains and modules that do not normodules are arranged within giant multienzyme submally cooperate with each other . Furthermore, units in the order in which they act. Protein-protein they have proposed that intersubunit protein-protein recinteractions between terminal docking domains of ognition is mediated by interactions between helices [11]. successive multienzymes promote their correct posi-Although the interface between successive multientioning within the assembly line, but because the overzymes likely also involves ACP and KS domains [15, all complex is not stable in vitro, the key interactions 16], it is clear that the intermolecular docking-domain have not been identified. We present here the NMR interaction is central to an understanding of the strucsolution structure of a 120 residue polypeptide repretural basis for discrimination between potential partners senting a typical pair of such domains, fused at their and, therefore, to attempts to improve hybrid PKSs.