The research described in the current proposal has the long-range goals of enabling the prediction of protein-protein interactions and the application of this knowledge to problems of biomedical relevance. An additional long-term goal is the fuller integration of Structural and Systems Biology.
Specific Aims i nclude: a) The development of three-dimensional structure-based methods to predict, on a genome-wide scale, whether and how two proteins interact. b) The integration of structural information with other sources of evidence as to protein-protein interactions. c) The application of the methods being developed to important biomedical problems. These research goals are motivated by a number of factors. First, cellular function is mediated by tens or even hundreds of thousands of protein-protein interactions yet these are generally hard to predict in advance or to measure accurately with high-throughput experimental techniques. A method that allows the computational prediction of such interactions would thus be of significant impact. Second, there are many more protein sequences than protein structures so it is necessary to find ways to amplify the information in protein databases if structure is to be fully integrated in genome scale research. The proposed research is intended to bridge this gap. A central element of the approach to be taken is the use of structural alignments to reveal novel functional relationships between proteins. Since structure is better conserved than sequence, these alignments can reveal new information. A novel structure-based method is introduced which exploits homology models and remote geometric relationships to amplify structural information. The evidence that is obtained is then combined with non-structural sources of evidence using Bayesian networks to yield a probability of whether two proteins interact. An important element in the proposed research strategy is the recognition that structural modeling on a large scale is necessarily imprecise so that it is necessary to use low resolution """"""""scoring functions for a given model that do not depend sensitively on atomic detail. Bayesian methods then allow the extraction of a clear signal from the underlying noise. The biological impact of the research will be enhanced through computational/experimental applications in areas where structural clues have the potential of discovering truly novel interactions. Validated predictions on adhesion proteins, nuclear hormone receptors and cytokine signaling proteins demonstrate the efficacy of the methodology. New applications to viral host interactions and to cancer signaling pathways are described.
The health relatedness of the proposed research arises from the fact that a better understanding of protein- protein interactions opens the way to a better understanding of the biology underlying human disease. Applications to interactions involved in viral-host interactions, and in cancer-related pathways serve to highlight this aspect of the proposed research.
|Zeiske, Tim; Baburajendran, Nithya; Kaczynska, Anna et al. (2018) Intrinsic DNA Shape Accounts for Affinity Differences between Hox-Cofactor Binding Sites. Cell Rep 24:2221-2230|
|Hirabayashi, Yusuke; Kwon, Seok-Kyu; Paek, Hunki et al. (2017) ER-mitochondria tethering by PDZD8 regulates Ca2+ dynamics in mammalian neurons. Science 358:623-630|
|Lopez-Rivera, Esther; Liu, Yangfan P; Verbitsky, Miguel et al. (2017) Genetic Drivers of Kidney Defects in the DiGeorge Syndrome. N Engl J Med 376:742-754|
|Hwang, Howook; Dey, Fabian; Petrey, Donald et al. (2017) Structure-based prediction of ligand-protein interactions on a genome-wide scale. Proc Natl Acad Sci U S A 114:13685-13690|
|Sheng, Ren; Jung, Da-Jung; Silkov, Antonina et al. (2016) Lipids Regulate Lck Protein Activity through Their Interactions with the Lck Src Homology 2 Domain. J Biol Chem 291:17639-50|
|Hwang, Howook; Petrey, Donald; Honig, Barry (2016) A hybrid method for protein-protein interface prediction. Protein Sci 25:159-65|
|Ma, Lijiang; Bayram, Yavuz; McLaughlin, Heather M et al. (2016) De novo missense variants in PPP1CB are associated with intellectual disability and congenital heart disease. Hum Genet 135:1399-1409|
|Harrison, Oliver J; Brasch, Julia; Lasso, Gorka et al. (2016) Structural basis of adhesive binding by desmocollins and desmogleins. Proc Natl Acad Sci U S A 113:7160-5|
|Park, Mi-Jeong; Sheng, Ren; Silkov, Antonina et al. (2016) SH2 Domains Serve as Lipid-Binding Modules for pTyr-Signaling Proteins. Mol Cell 62:7-20|
|Westphalen, C Benedikt; Takemoto, Yoshihiro; Tanaka, Takayuki et al. (2016) Dclk1 Defines Quiescent Pancreatic Progenitors that Promote Injury-Induced Regeneration and Tumorigenesis. Cell Stem Cell 18:441-55|
Showing the most recent 10 out of 88 publications