Chemistry & Biology
Volume 18, Issue 9, 23 September 2011, Pages 1143-1152
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Article
A Systematic Family-wide Investigation Reveals that ∼30% of Mammalian PDZ Domains Engage in PDZ-PDZ Interactions

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Summary

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.

Highlights

► PDZ-PDZ interactions were investigated on a proteome-wide scale by combining the throughput of protein microarray technology with the fidelity of solution-phase fluorescence polarization ► Thirty-seven PDZ-PDZ interactions were identified, and a representative subset of these interactions was investigated biochemically and found to mediate protein-protein interactions in the context of their full-length proteins ► Overall, PDZ-PDZ dimerization was found to be a much more frequently used binding mode than was previously appreciated

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These authors contributed equally to this work

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Present address: Merrimack Pharmaceuticals, Inc., Cambridge, MA 02139, USA