The emerging contribution of sequence context to the specificity of protein interactions mediated by PDZ domains

The canonical binding mode of PDZ domains to target motifs involves a small interface, unlikely to fully account for PDZ‐target interaction specificities. Here, we review recent work on sequence context, defined as the regions surrounding not only the PDZ domains but also their target motifs. We also address the theoretical problem of defining the core of PDZ domains and the practical issue of designing PDZ constructs. Sequence context is found to introduce structural diversity, to impact the stability and solubility of constructs, and to deeply influence binding affinity and specificity, thereby increasing the difficulty of predicting PDZ‐motif interactions. We expect that sequence context will have similar importance for other protein interactions mediated by globular domains binding to short linear motifs.