title: A systematic family-wide investigation reveals that ~30% of mammalian PDZ domains engage in PDZ-PDZ interactions.
abstract: PDZ domains are independently folded modules that typically mediate protein-protein interactions by binding to the C termini of their target proteins. However, in a few instances, PDZ domains have been reported to dimerize with other PDZ domains. To investigate this noncanonical-binding mode further, we used protein microarrays comprising virtually every mouse PDZ domain to systematically query all possible PDZ-PDZ pairs. We then used fluorescence polarization to retest and quantify interactions and coaffinity purification to test biophysically validated interactions in the context of their full-length proteins. Overall, we discovered 37 PDZ-PDZ interactions involving 46 PDZ domains (~30% of all PDZ domains tested), revealing that dimerization is a more frequently used binding mode than was previously appreciated. This suggests that many PDZ domains evolved to form multiprotein complexes by simultaneously interacting with more than one ligand.
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Bryan H
authors.initials: BH
authors.lastname: Chang
authors.forename: Taranjit S
authors.initials: TS
authors.lastname: Gujral
authors.forename: Ethan S
authors.initials: ES
authors.lastname: Karp
authors.forename: Raghida
authors.initials: R
authors.lastname: BuKhalid
authors.forename: Viara P
authors.initials: VP
authors.lastname: Grantcharova
authors.forename: Gavin
authors.initials: G
authors.lastname: MacBeath
mesh_terms: D000818:Animals; D002460:Cell Line; D019281:Dimerization; D005454:Fluorescence Polarization; D006801:Humans; D051379:Mice; D054731:PDZ Domains; D040081:Protein Array Analysis; D011485:Protein Binding; D060066:Protein Interaction Maps; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D020543:Proteome / Q000737:chemistry / Q000378:metabolism
chemical_list: D011506:Proteins; D020543:Proteome