Shorter is better

To the editor:

As the final structure–function of proteins depends on the folding environment, protein primary structure does not necessarily guarantee a unique tertiary structure, functionality, or even solubility. The paper by Matsuura et al.¹ demonstrated that protein thermal stability could be altered by engineered random peptides (tags) at the C terminus. It provides a great potential for protein improvements and stabilization. One of the limitations of this approach is that the active peptide is covalently linked to the target protein limiting the sites in the protein that it can interact with.

A year ago we demonstrated that "unattached peptides" could modulate the function of a model protein, tryptophan repressor, in vivo and in vitro. One tripeptide, for example, mimicked the inducer and resulted in loss of repression (Fenton et al. 1998)². One obvious application of our approach is "protein therapy," in which the coding sequence of target protein would not be altered, but its activity could be modulated by a short peptide. Early genetic research demonstrated that mutants within the same cistron could complement each other. This restoration of function of dead proteins, as for example in mutant/mutant interaction (Storbakk et al 1996)³, also questions the uniqueness of tertiary/quaternary structure for functionality of the protein. Together with the chaperones and foldases, the current findings open doors to unlimited applications in biotechnology. If therapeutic proteins are reduced to short peptides⁴ and proteins can be modulated by short transportable peptides, perhaps for therapeutics shorter is better.