Changing the Apoptosis Pathway through Evolutionary Protein Design
By D. Shultis, Pralay Mitra, Xiaoqiang Huang, Jarrett S Johnson, Naureen Aslam Khattak, F. Gray, Clint Piper, Jeff Czajka, Logan Hansen, B. Wan and 10 more. 2019
21 citations recorded by the source corpus.
One obstacle in de novo protein design is the vast sequence space that needs to be searched through to obtain functional proteins. We developed a new method using structural profiles created from evolutionarily related proteins to constrain the simulation search process, with functions specified by atomic-level ligand- protein binding interactions. The approach was applied to redesigning the BIR3 domain of the X-linked inhibitor of apoptosis protein (XIAP), whose primary function is to suppress the cell death by inhibiting caspase-9 activity; however, the function of the wild-type XIAP can be eliminated by the binding of Smac peptides. Isothermal calorimetry and luminescence assay reveal that the designed XIAP domains can bind strongly with the Smac peptides but do not significantly inhibit the caspase-9 proteolytic activity in vitro compared with the wild-type XIAP protein. Detailed mutation assay experiments suggest that the binding specificity in the designs is essentially determined by the interplay of structural profile and physical interactions, which demonstrates the potential to modify apoptosis pathways through computational design.
Subfields: Genetics, Molecular Biology
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In Molecular Biology
- Robin Pearce
- Xiaoqiang Huang
- Dani Setiawan
- Yang Zhang
- Jianyi Yang
- Ambrish Roy
- Sitao Wu
- Chengxin Zhang
Citations in the corpus
- EvoDesign: Designing protein-protein binding interactions using evolutionary interface profiles in conjunction with an optimized physical energy function (2019, methodology): “The rationale behind designing non-interface residues is that introducing mutations in the interface may have destabilizing effects on the whole protein or lead to suboptimal packing [8, 33, 34].”