Introduction:
Conformational transitions in proteins play important roles in many biological processes. To improve our understanding of such processes, and to develop novel molecules for applications in nanobiotechnology, we are attempting the de novo design of peptides that switch structural state.
Our lab has designed three switch peptides based on canonical coiled-coil motifs, which change conformation in response to different factors.
Template-alpha T is a dimeric, parallel coiled coil that undergoes a heat-inducible
switch to beta-structure (Ciani et al., 2002). This was achieved by introducing beta-structure character into the sequence
while minimising disruption to the residues important for the formation of the coiled coil.
This work is further discussed in:
"A designed system for assessing how sequence affects alpha-to-beta conformational transitions in proteins"
Ciani et al, J. Biol. Chem 277 10150-10155 (2002), (
Abstract)
The CSP(Coiled-coil Switch Peptides) are designed to respond to the addition of disulfide-reducing agents.
The designs are based on heptad and related sequence motifs characteristic of two-helix coiled coils. The terminal
residues are made cysteine to allow the two different sequence motifs to be expressed in different redox states.
A parallel coiled-coil dimer (leucine zipper) is promoted in the reduced state, and a monomeric
anti-parallel, two-helix coiled coil (helical hairpin) in the intra-molecularly oxidized state.
This work is further discussed in:
"Sequence and Structural Duality: Designing Peptides to Adopt Two Stable Conformations"
MJ Pandya et al J. Am. Chem. Soc 126 17016-17024, (2004),
Abstract)
ZiCo is a reversible switch between two different folded conformations. This design is based on the idea that two folds can be obtained by varying the binding partner, shifting the equilibrium simply by addition of the appropriate ligand. In order to design such a system we have turned to a non-covalent interaction, metal binding, as the driving force. To date, the design of metal-binding sites by others has primarily been to stabilize a previously unstructured or partially structured peptide, or to incorporate a metal-binding site onto a pre-formed protein scaffold. However, they have not been previously exploited to instigate a conformational switch. To our knowledge ZiCo is the first such system