Stereochemical Preferences Modulate Affinity and Selectivity among Five PDZ Domains that Bind CFTR: Comparative Structural and Sequence Analyses

摘要: Summary PDZ domain interactions are involved in signaling and trafficking pathways that coordinate crucial cellular processes. Alignment-based binding motifs identify the few most favorable residues at certain positions along peptide backbone. However, sequences bind CAL (CFTR-associated ligand) reveal only a degenerate motif overpredicts true number of high-affinity interactors. Here, we combine extended peptide-array analysis with biochemical techniques to show non-motif "modulator" influence binding. The crystallographic structures 13 CAL:peptide complexes defined, but accommodating stereochemical environments positions, which reflected modulator preferences uncovered by multisequence substitutional arrays. These facilitate identification differentially affect NHERF As result, they also help determine specificity network regulates CFTR apical membrane.