Molecular design of orthogonal stacking system at the complex interface of HtrA PDZ domain with its peptide ligands

Dingwa Zhang, Deyong He, Xiaoliang Pan, Yaping Xu, Lijun Liu

Abstract


The high temperature requirement A (HtrA) protease plays a crucial role in protein quality control and cell fate. The enzyme contains a catalytic protease domain and a regulatory PDZ domain; the latter determines the substrate specificity of the former by specifically binding to the C-terminal hydrophobic stretch of its partner proteins. Previously, a pentapeptide ligand H3C1 was identified as the potential binder of HtrA PDZ domain using phage display technique. Here, we analyze an orthogonal π-cation-π stacking system at the crystal domain–peptide complex interface by integrating theoretical calculations and experimental assays. We demonstrate that there is a strong (positive) synergistic effect between the two wings of the stacking system; breaking of cation-π interaction in one wing can largely impair the interaction strength of another wing. The π-electron contributes primarily to the synergistic effect, although geometric property is also (marginally) responsible for it. Next, we investigate the systematic combinations between the four aromatic amino acids (Phe, Tyr, Trp and His) plus one non-aromatic amino acid (Ala) at the two wings of π-cation-π stacking, and find that two aromatic substitutions (Phe-4Tyr and Phe-4Trp) at a wing can considerably and moderately improve peptide affinity by 3.2-fold and 1.5-fold, respectively, whereas the non-aromatic mutations at each wing and both can significantly reduce the affinity with Kd increase from 1.8 μM (wild type) to 34 and 160 μM (single-point mutations) as well as 210 μM (double-point mutation), suggesting that just breaking of one wing can substantially undermine the synergism of orthogonal π-cation-π stacking.


Keywords


protease; HtrA PDZ domain; peptide ligand; orthogonal π-cation-π stacking; synergistic effect

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DOI: https://doi.org/10.2298/JSC181221029Z

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