PDZ (PSD-95/Discs-large/ZO1) domains are important protein domains involved in many biological processes. They are defined by their ability to bind specific C-terminal regions to form functional complexes. Current understanding of binding involves sets of pairwise interactions in the 2 contiguous β strands 2 and 3, 2 coil regions flanking β strand 2, and α-helix 2. To include multibody packing interactions as well as a more intuitive description of binding and specificity, a model based on a knob-socket (KS) analysis of PDZ-peptide crystal structures has been developed based loosely on an “outfit” grouping of interactions. This site can be separated into 4 binding regions—the “cap”, “shirt”, “jacket” and “sock”. The cap consists of the coil region n terminal to β strand 2 and is associated with affinity and recruitment for sampling of the c-terminal residues. Binding specificity is most attributed with the sheet and helix regions, which are categorized as shirt and jacket respectively. Depending on the class, consistent patterns of binding can be observed within these regions. For the shirt, specificity is determined by sockets favoring β sheet formation, for the jacket, specificity is seen as knob residues packing into their respective sockets. In both the shirt and jacket, the amino-acid make-up of the sockets influences specificity. Finally, the sock region is defined as the coil which is c-terminal to β strand 2 and interacts with the N-terminal residues. The role of the sock region is ambiguous, but typically exhibits a variety of interactions serving to stabilize the n terminus of the peptide, especially for peptides over 6 residues in length. PDZ domains have been classified into 4 classes, which exhibit consistent binding patterns within the 4 binding regions.
Lasse et al. (Sun,) studied this question.