Structural components of SCAN‐domain dimerizations

Abstract

The SCAN or leucine‐rich domain has been characterized as a highly conserved sequence in zinc finger transcription factors that mediates selective dimer formation between SCAN‐domain‐containing proteins. In order to accommodate various SCAN‐domain sequence features, a minimal functional folding unit was defined on the premise of proper structural folding and biochemical binding. The 58‐amino acid minimal functional units derived from each of four SCAN‐domain protein families were subjected to a three‐dimensional position‐specific scoring matrix (3D‐PSSM) and ungapped threading analysis. The resulting fold prediction represented the SCAN‐domain's minimal functional unit as a bundle of three alpha helices folded to a core structure. In addition, the minimal functional folding unit biochemically retained the selective dimerization properties of the native proteins. In order to elucidate the structural components within the SCAN‐domain that engage in binding interactions, we attempted to correlate the physicochemical helix properties, as represented by a hydropathy profile, with the experimental dimerization selectivities. The amino‐terminal helix revealed the highest diversity measure among the three helices of the minimal functional unit and is therefore likely to offer critical surface‐exposed binding residues. Indeed, by interchanging the amino‐terminal helix between SCAN‐domains without alteration of their structural frames consisting of conserved hydrophobic residues, a modulation of binding preferences was demonstrated. The minimal functional folding unit of SCAN‐domains may therefore contain within the amino‐terminal alpha helix structural components that determine selective dimerization patterns and combinatorial control of transcription factors. Proteins 2004.