Journal
STRUCTURE
Volume 22, Issue 1, Pages 82-93Publisher
CELL PRESS
DOI: 10.1016/j.str.2013.09.019
Keywords
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Funding
- National Institutes of Health [R01-DK075309, R01-HG004499, T32-GM008704, T32-DK007301]
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PDZ domain interactions are involved in signaling and trafficking pathways that coordinate crucial cellular processes. Alignment-based PDZ binding motifs identify the few most favorable residues at certain positions along the peptide backbone. However, sequences that bind the CAL (CFTR-associated ligand) PDZ domain reveal only a degenerate motif that overpredicts the true number of high-affinity interactors. Here, we combine extended peptide-array motif analysis with biochemical techniques to show that non-motif modulator residues influence CAL binding. The crystallographic structures of 13 CAL: peptide complexes reveal defined, but accommodating stereochemical environments at non-motif positions, which are reflected in modulator preferences uncovered by multisequence substitutional arrays. These preferences facilitate the identification of high-affinity CAL binding sequences and differentially affect CAL and NHERF PDZ binding. As a result, they also help determine the specificity of a PDZ domain network that regulates the trafficking of CFTR at the apical membrane.
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