title: 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.
authors.affiliation: Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Korea.
authors.forename: Jinho
authors.initials: J
authors.lastname: Kim
authors.forename: Inhae
authors.initials: I
authors.lastname: Kim
authors.forename: Jae-Seong
authors.initials: JS
authors.lastname: Yang
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Shin
authors.forename: Jihye
authors.initials: J
authors.lastname: Hwang
authors.forename: Solip
authors.initials: S
authors.lastname: Park
authors.forename: Yoon Sup
authors.initials: YS
authors.lastname: Choi
authors.forename: Sanguk
authors.initials: S
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D005075:Biological Evolution; D030562:Databases, Protein; D004194:Disease / Q000235:genetics; D019143:Evolution, Molecular; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D009154:Mutation; D009420:Nervous System / Q000378:metabolism; D054731:PDZ Domains; D011485:Protein Binding; D011506:Proteins; D013329:Structure-Activity Relationship; D014714:Vertebrates / Q000235:genetics
chemical_list: D008024:Ligands; D011506:Proteins