The PDZ Domain as a Complex Adaptive System

Abstract

Specific protein associations define the wiring of protein interaction networks and thus control the organization and functioning of the cell as a whole. Peptide recognition by PDZ and other protein interaction domains represents one of the best-studied classes of specific protein associations. However, a mechanistic understanding of the relationship between selectivity and promiscuity commonly observed in the interactions mediated by peptide recognition modules as well as its functional meaning remain elusive. To address these questions in a comprehensive manner, two large populations of artificial and natural peptide ligands of six archetypal PDZ domains from the synaptic proteins PSD95 and SAP97 were generated by target-assisted iterative screening (TAIS) of combinatorial peptide libraries and by synthesis of proteomic fragments, correspondingly. A comparative statistical analysis of affinity-ranked artificial and natural ligands yielded a comprehensive picture of known and novel PDZ ligand specificity determinants, revealing a hitherto unappreciated combination of specificity and adaptive plasticity inherent to PDZ domain recognition. We propose a reconceptualization of the PDZ domain in terms of a complex adaptive system representing a flexible compromise between the rigid order of exquisite specificity and the chaos of unselective promiscuity, which has evolved to mediate two mutually contradictory properties required of such higher order sub-cellular organizations as synapses, cell junctions, and others -organizational structure and organizational plasticity/ adaptability. The generalization of this reconceptualization in regard to other protein interaction modules and specific protein associations is consistent with the image of the cell as a complex adaptive macromolecular system as opposed to clockwork.

Distinct Ligand Specificity of the Tiam1 and Tiam2 PDZ Domains

“…The fact that mutations in S 0 and S -2 pockets were synergistic in changing the Tiam1 PDZ domain specificity hints that these couplings might exist. Our results support the notion that PDZ affinity and specificity are regulated by determinants spread across the entire binding site rather by a few discrete sub-sites (8, 27, 49, 50). This feature would likely enable the broad range of PDZ specificities needed to accommodate interactions with many potential ligands, but would also complicate the design of novel specificities.…”

Learning Sequence Determinants of Protein:Protein Interaction Specificity with Sparse Graphical Models

“…Due to their size and easy availability, PDZ domains form a ''model system'' for studying protein-protein interactions (Sheng and Sala, 2001;Kurakin et al, 2007;Tonikian et al, 2008;Chen et al, 2008). They are involved in formation of protein complexes that are involved in cellular signal transduction and neural circuitry (Sheng and Sala, 2001) and so make an interesting test case from the point of view of protein engineering (Fuh et al, 2000) and drug design (Saro et al, 2007).…”

Novel Mediators of Amyloid Precursor Protein Signaling

“…1B), which indicates that, although preferred, Trp or other hydrophobic residues are not required at the −1 position. Additionally, the fact that only 26 out of 93 SAP peptides were positive for binding to Mint1-PDZ-2 clearly shows that in some cases, the last three positions in the consensus peptide sequence T/S-X-V are not sufficient to determine an interaction, and that other residues located upstream of the C-terminus must play an important role in this process, as suggested by other investigators (Niethammer et al, 1998; Birrane et al, 2003; Appleton et al, 2006; Kurakin et al, 2007). Alignment of the sequences of the various interacting artificial peptides allowed us to deduce a strict consensus sequence, X-W-V/L (Supplementary Fig.…”

“…In addition to this analysis, we performed phage ELISAs for both PDZs using 93 class I artificial peptides containing C-terminal Val, which were isolated for PDZ domain interactors of the Synapse-Associated Protein (SAP) family in our previous work (Kurakin et al, 2007). We did not detect any interactions between these SAP-PDZ interactors and the Mint1 PDZ-1, which is compatible with the profile described above.…”