Rewiring of PDZ Domain-Ligand Interaction Network Contributed to Eukaryotic Evolution

Abstract

PDZ domain-mediated interactions have greatly expanded during metazoan evolution, becoming important for controlling signal flow via the assembly of multiple signaling components. The evolutionary history of PDZ domain-mediated interactions has never been explored at the molecular level. It is of great interest to understand how PDZ domain-ligand interactions emerged and how they become rewired during evolution. Here, we constructed the first human PDZ domain-ligand interaction network (PDZNet) together with binding motif sequences and interaction strengths of ligands. PDZNet includes 1,213 interactions between 97 human PDZ proteins and 591 ligands that connect most PDZ protein-mediated interactions (98%) in a large single network via shared ligands. We examined the rewiring of PDZ domain-ligand interactions throughout eukaryotic evolution by tracing changes in the C-terminal binding motif sequences of the PDZ ligands. We found that interaction rewiring by sequence mutation frequently occurred throughout evolution, largely contributing to the growth of PDZNet. The rewiring of PDZ domain-ligand interactions provided an effective means of functional innovations in nervous system development. Our findings provide empirical evidence for a network evolution model that highlights the rewiring of interactions as a mechanism for the development of new protein functions. PDZNet will be a valuable resource to further characterize the organization of the PDZ domain-mediated signaling proteome.

Stereochemical Determinants of C-terminal Specificity in PDZ Peptide-binding Domains

“…Interaction data suggest that PDZ target preferences are hard-wired into the PDZ domain itself (18,65,66). Indeed, one of the hallmarks of organismal complexity is the expansion of the number of PDZ domains and the rewiring of their interactions (66 -68).…”

Ligand-Induced Dynamic Changes in Extended PDZ Domains from NHERF1

“…So far the binding site sequence variation or static view of the X-ray structures has failed to provide an adequate rationale for the extraordinary ability of the PDZ1 domain to recognize diverse targets 30; 31; 32 . Traditionally the high propensity for mutations in the active site of the PDZ domains has been cited as the primary source of ligand specificity 33; 34 . However the generic target affinity and biological function of the canonical PDZ domain can be altered dramatically by multiple factors, including conformational dynamics of the isolated 35; 36 or coupled domains 18; 37 and unique structural modifications 38; 39; 40; 41; 42 .…”

Zeta Inhibitory Peptide Disrupts Electrostatic Interactions That Maintain Atypical Protein Kinase C in Its Active Conformation on the Scaffold p62

“…Atypical PKCs differ from conventional and novel PKCs by having an N-terminal Phox and Bem1 (PB1) domain, a proteinprotein interaction module that homodimerizes with the PB1 domain of proteins such as the scaffold p62, also known as sequestosome 1 (SQSTM1) and zeta-interacting protein (15)(16)(17). In addition, they contain a Type III PDZ ligand that is predicted to target aPKCs to PDZ domain proteins that bind Type III ligands (18,19). This tethering to protein scaffolds is likely the key determinant in specificity of signaling by aPKCs, particularly given their exceptionally low catalytic rate (1-2 orders of magnitude lower than that of conventional PKC isozymes, depending on the substrate (20)).…”