Novel interactions of the TRTK12 peptide with S100 protein family members: specificity and thermodynamic...

The S100 protein family consists of small, dimeric proteins that exert their biological functions in response to changing calcium concentrations. S100B is the best-studied member and has been shown to interact with more than 20 binding partners in a calcium-dependent manner. The TRTK12 peptide, derived from the consensus binding sequence for S100B, has previously been found to interact with S100A1 and has been proposed to be a general binding partner of the S100 family. To test this hypothesis and gain a better understanding of the specificity of binding for the S100 proteins, 16 members of the human S100 family were screened against this peptide and its alanine variants. Novel interactions were found with only two family members, S100P and S100A2, indicating that TRTK12 selectively interacts with a small subset of the S100 proteins. Substantial promiscuity was observed in the binding site of S100B thereby accommodating variations in the peptide sequence, while S100A1, S100A2, and S100P exhibited larger differences in the binding constants for the TRTK12 alanine variants. This suggests that single-point substitutions can be used to selectively modulate the affinity of TRTK12 peptides for individual S100 proteins. This study has important implications for the rational drug design of inhibitors for the S100 proteins, which are involved in a variety of cancers and neurodegenerative diseases.