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Stereochemical preferences modulate affinity and selectivity among five PDZ domains that bind CFTR: comparative structural and sequence analyses.


ABSTRACT: 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.

SUBMITTER: Amacher JF 

PROVIDER: S-EPMC3947174 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Stereochemical preferences modulate affinity and selectivity among five PDZ domains that bind CFTR: comparative structural and sequence analyses.

Amacher Jeanine F JF   Cushing Patrick R PR   Brooks Lionel L   Boisguerin Prisca P   Madden Dean R DR  

Structure (London, England : 1993) 20131107 1


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 sh  ...[more]

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