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Towards a better understanding of protein interaction specificities in cell signalling - PDZ domains in the spotlight of computational and experimental approaches

Abstract : PDZ domains recognize C-terminal PDZ-binding motifs (PBMs) thereby mediating protein interactions that are often involved in cell polarity regulation. In this thesis, we studied under various aspects the specificity of PDZ-PBM interactions. We identified weak performances of two published predictors for interactions between core PDZ domains and short PBMs. Next, we developed protocols based on BIAcore and HoldUp to experimentally validate on a large scale predicted PDZ-PBM interactions and to study the influence of sequence context (e.g. flanking regions or neighbouring domains) of PDZs and PBMs on their interaction affinity and specificity. We identified new potential interactions involving the human PDZ proteins MAGI1 and SCRIB underpinning their implication in G protein signalling pathways. A literature survey combined with our own findings reveal structural mechanisms, by which sequence context influences PDZ interaction affinities and specificities. We have discussed those in a published review. Insights gained from this thesis may positively impact future studies on PDZ-PBM interactions in particular and on domain-linear motif interactions in general.
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Katja Luck. Towards a better understanding of protein interaction specificities in cell signalling - PDZ domains in the spotlight of computational and experimental approaches. Bioengineering. Université de Strasbourg, 2012. English. ⟨NNT : 2012STRAJ083⟩. ⟨tel-00813491⟩

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