How to untwist an alpha-helix: Structural principles of an alpha-helical barrel

Recent crystallographic studies have revealed that 12 alpha -helices can pa ck in an anti-parallel fashion to form a hollow cylinder of nearly uniform radius. In this architecture, which we refer to as an alpha -barrel, the he lices are inclined with respect to the cylindrical axis, and thus they curv e and twist. As with conventional coiled-coils, the helices of the barrel a ssociate via "knobs-into-holes" interactions; however, their packing is dis tinct in several important ways. First, the alpha -barrel helices untwist i n comparison with the helices found in two-stranded coiled-coils and, as a consequence of this distortion, their knobs approach closely one end of the complementary holes. This effect defines a requirement for particular size and shape of the protruding residues, and it is associated with a relative axial translation of the paired helices. Second, as each helix packs later ally with two neighbours, the helices have two sequence patterns that are p hased to match the two interfaces. The two types of interface are not equiv alent and, as one travels around the circumference of the cylinder's interi or, they alternate between one type where the knobs approach the holes stra ight-on, and a second type in which they are inclined. The choice of amino acid depends on the interface type, with small hydrophobic side-chains pref erred for the direct contacts and larger aliphatic side-chains for the incl ined contacts. Third, small residues are found preferentially on the inside of the tube, in order to make the "wedge" angle between helices compatible with a 12-member tube. Finally, hydrogen-bonding interactions of side-chai ns within and between helices support the assembly. Using these salient str uctural features, we present a sequence template that is compatible with so me underlying rules for the packing of helices in the barrel, and which may have application to the design of higher-order assemblies from peptides, s uch as nano-tubes. We discuss the general implications of relative axial tr anslation in coiled-coils and, in particular, the potential role that this movement could play in allosteric mechanisms. (C) 2001 Academic Press.