Abstract
The orientation of alpha-helical chains in two-stranded coiled-coils has been shown to be determined by the presence of favorable interchain electrostatic interactions. In this study, we used de novo designed 35-residue peptides to show that when interchain electrostatic interactions are not a factor in coiled-coil formation, the relative positions of Ala residues in the middle heptad can control the parallel or antiparallel orientation of alpha-helical chains in coiled-coils. The peptides formed four-stranded coiled-coils where the helices are either all-parallel or all-antiparallel with respect to their nearest neighbor. The common structural element in these four-stranded coiled-coils is an alternating pair of Ala and Leu residues (Ala-Leu-Ala-Leu) in each of the two planes in the middle heptad. These results indicate that both the relative positions of the Ala residues in the hydrophobic core and the interchain electrostatic interactions between charged residues in the e and g positions should be considered in designing coiled-coils with the desired number of strands in the multiple-stranded assembly. These design elements are also important in orienting functional groups or domains attached to the terminals ends of a coiled-coil carrier.
Highlights
The simplicity and regularity of the coiled-coil has made this motif an excellent model for studying protein folding and protein-protein interactions
The crosssectional diagrams of the middle heptads of representative peptides 2E16 and 2K16 in ␣-helical forms (Fig. 2, A and B, respectively) show that the same potential interchain electrostatic interactions can occur in the e and g positions whether the chains are viewed from the N or the C termini
The type of electrostatic interaction is identical in the parallel or antiparallel orientation, that is, with regard to attractions or repulsions, structurally these interactions are not necessarily identical
Summary
The simplicity and regularity of the coiled-coil has made this motif an excellent model for studying protein folding and protein-protein interactions. There is a similar attempt to understand the role of interchain electrostatic interactions in controlling the parallel or antiparallel orientation of ␣-helical chains in two-stranded coiled-coils. It has been shown that the favored chain orientation is one that results in interchain electrostatic attractions (Monera et al, 1993, 1994) It is not known whether or not the type of hydrophobic packing in the interface controls the parallel or antiparallel orientation of ␣-helical chains in coiled-coils. In order to address this question, we designed coiled-coils where interchain electrostatic interactions are not a determinant of chain orientation and, the formation of parallel or antiparallel coiled-coils become mainly a function of the type of hydrophobic packing in the interface
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