Abstract
Selective dimerization of the basic-region leucine-zipper (bZIP) transcription factors presents a vivid example of how a high degree of interaction specificity can be achieved within a family of structurally similar proteins. The coiled-coil motif that mediates homo- or hetero-dimerization of the bZIP proteins has been intensively studied, and a variety of methods have been proposed to predict these interactions from sequence data. In this work, we used a large quantitative set of 4,549 bZIP coiled-coil interactions to develop a predictive model that exploits knowledge of structurally conserved residue-residue interactions in the coiled-coil motif. Our model, which expresses interaction energies as a sum of interpretable residue-pair and triplet terms, achieves a correlation with experimental binding free energies of R = 0.68 and significantly out-performs other scoring functions. To use our model in protein design applications, we devised a strategy in which synthetic peptides are built by assembling 7-residue native-protein heptad modules into new combinations. An integer linear program was used to find the optimal combination of heptads to bind selectively to a target human bZIP coiled coil, but not to target paralogs. Using this approach, we designed peptides to interact with the bZIP domains from human JUN, XBP1, ATF4 and ATF5. Testing more than 132 candidate protein complexes using a fluorescence resonance energy transfer assay confirmed the formation of tight and selective heterodimers between the designed peptides and their targets. This approach can be used to make inhibitors of native proteins, or to develop novel peptides for applications in synthetic biology or nanotechnology.
Highlights
IntroductionThe basic-region leucine-zipper (bZIP) transcription factors pose a compelling problem to scientists interested in protein-protein interaction specificity
Protein interactions are important for all life processes, and an ability to rationally control or selectively inhibit protein complexes would impact studies of cellular structure, biological information processing, molecular regulatory processes and other phenomena
We demonstrated experimentally that the designed proteins bind tightly and to a number of human basic-region leucine-zipper (bZIP) that regulate important processes including stress responses and oncogenesis
Summary
The basic-region leucine-zipper (bZIP) transcription factors pose a compelling problem to scientists interested in protein-protein interaction specificity. Biochemical assays using highly purified components have established that 53 human bZIP coiled coils span at least 38 distinct interaction profiles, defined by the strength of a protein’s binding to each of 53 possible interaction partners [1]. This observation demonstrates that an enormous amount of interaction information is encoded compactly in coiled-coil sequences. A fundamental challenge for computational structural biologists is to decipher the code by which sequence determines interaction selectivity, and the bZIP proteins present an outstanding opportunity to tackle this problem. Because many other interaction domains mediate specific interactions that broadly influence biology, developing methods that allow us to interpret, predict and manipulate the sequence-interaction code of proteins is a compelling objective
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