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Improved affinity at the cost of decreased specificity: a recurring theme in PDZ-peptide interactions.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. (Ivarsson)
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 34269Article in journal (Refereed) Published
Abstract [en]

The E6 protein from human papillomavirus (HPV) plays an important role during productive infection and is a potential drug target. We have previously designed a high affinity bivalent protein binder for the E6 protein, a fusion between a helix from the E6 associated protein and PDZØ9, an engineered variant (L391F/K392M) of the second PDZ domain from synapse associated protein 97 (SAP97 PDZ2). How the substitutions improve the affinity of SAP97 PDZ2 for HPV E6 is not clear and it is not known to what extent they affect the specificity for cellular targets. Here, we explore the specificity of wild type SAP97 PDZ2 and PDZØ9 through proteomic peptide phage display. In addition, we employ a double mutant cycle of SAP97 PDZ2 in which the binding kinetics for nine identified potential cellular peptide ligands are measured and compared with those for the C-terminal E6 peptide. The results demonstrate that PDZØ9 has an increased affinity for all peptides, but at the cost of specificity. Furthermore, there is a peptide dependent coupling free energy between the side chains at positions 391 and 392. This corroborates our previous allosteric model for PDZ domains, involving sampling of intramolecular energetic pathways.

Place, publisher, year, edition, pages
2016. Vol. 6, 34269
National Category
Natural Sciences
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:uu:diva-306579DOI: 10.1038/srep34269ISI: 000384758300001PubMedID: 27694853OAI: oai:DiVA.org:uu-306579DiVA: diva2:1040843
Funder
Swedish Research Council
Available from: 2016-10-29 Created: 2016-10-29 Last updated: 2016-11-09Bibliographically approved

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Karlsson, O AndreasSundell, Gustav NAndersson, EvaIvarsson, YlvaJemth, Per
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