Adaptations of the helix-grip fold for ligand binding and catalysis in the START domain superfamily.
With a protein structure comparison, an iterative database search with sequence 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 large, previously underappreciated superfamily that we call the START superfamily. In addition to the classical START domains that are primarily involved in eukaryotic signaling mediated by lipid binding and the birch antigen family that consists of plant proteins implicated in stress/pathogen response, the START superfamily includes bacterial polyketide cyclases/aromatases (e.g., TcmN and WhiE VI) and two families of previously uncharacterized proteins. The identification of this domain provides a structural prediction of an important class of enzymes involved in polyketide antibiotic synthesis and allows the prediction of their active site. It is predicted that all START 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/aromatase and an RNase. Thus, the START domain superfamily is a rare case of the adaptation of a protein fold with a conserved ligand-binding mode for both a broad variety of catalytic activities and noncatalytic regulatory functions. Proteins 2001;43:134-144.
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
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Iyer
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Koonin
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Aravind
D000485:Allergens / Q000737:chemistry*; D000595:Amino Acid Sequence; D001665:Binding Sites; D002352:Carrier Proteins; D002384:Catalysis; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry*; D008958:Models, Molecular; D010802:Phylogeny; D010940:Plant Proteins / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D014197:Trees
D000485:Allergens; D002352:Carrier Proteins; D008024:Ligands; D008565:Membrane Proteins; D010940:Plant Proteins; C105684:STARD3 protein, human