Due to its critical role in
cancer progression, interactions between
laminin-1 and the 67 kDa
Laminin-
Binding Protein (the 67 kDa LBP) have been the focus of a number of structural and
biological studies. As
laminin-1 is such a large and complex molecule, research interests have turned to the investigation of bioactive
peptides derived from binding domains of
laminin-1. Two
peptides of interest,
CDPGYIGSR (
peptide 11) and
YIGSR, both derived from the beta1 chain of
laminin-1, have been shown to block invasion of basement membranes by
tumor cells. Substituting the C-terminal
arginine to
lysine, a conservative substitution, results in a loss of
peptide antimetastatic activity. This difference in bioactivity has been attributed, based on numerous modeling studies of free
peptide conformations, to structural differences between
YIGSR and YIGSK. Yet the nature of the 'active' free
peptide backbone conformation has been a matter of debate and controversy. In order to test the validity of the structural modeling claims, we have undertaken detailed conformational studies of the two
laminin-1 derived
peptides YIGSR and
CDPGYIGSR along with the biologically inactive YIGSK analog by two-dimensional
solution 1H NMR spectroscopy in three different
solvent systems. Herein we report that although both the active (
YIGSR,
CDPGYIGSR) and the inactive (YIGSK)
peptides can adopt several closely related conformations in
solution, the two
peptides share similar conformational preferences, and there are no significant structural differences between the active and inactive
peptides, contrary to previously reported modeling data. We conclude that the basis of the
peptide biological activity, in contrast to published models, cannot be attributed to well-defined structural preferences of the free
peptides. We infer that the difference in bioactivity observed between
YIGSR and YIGSK originates primarily from the chemical nature of the
arginine versus
lysine sidechain substitution, rather than being due to a structural change in the free
peptide conformations.