Adaptations of the helix-grip fold for ligand binding and catalysis in theSTART domain superfamily

With a protein structure comparison, an iterative database search with sequ ence profiles, and a multiple-alignment analysis, we show that two domains with the helix-grip fold, the star-related lipid-transfer (START) domain of the MLN64 protein and the birch allergen, are homologous. They define a la rge, previously underappreciated superfamily that we call the START superfa mily. In addition to the classical START domains that are primarily involve d in eukaryotic signaling mediated by lipid binding and the birch antigen f amily that consists of plant proteins implicated in stress/pathogen respons e, the START superfamily includes bacterial polyketide cyclases/aromatases (e.g., TcmN and WhiE VI) and two families of previously uncharacterized pro teins, The identification of this domain provides a structural prediction o f an important class of enzymes involved in polyketide antibiotic synthesis and allows the prediction of their active site. It is predicted that all S TART domains contain a similar ligand-binding pocket, Modifications of this pocket determine the ligand-binding specificity and may also be the basis for at least two distinct enzymatic activities, those of a cyclase/aromatas e and an RNase. Thus, the START domain superfamily is a rare case of the ad aptation of a protein fold with a conserved ligand-binding mode for both a broad variety of catalytic activities and noncatalytic regulatory functions . Published 2001 Wiley-Liss, Inc.(dagger)