Protein modifications, mouse genetics, cancer, cytoskeleton, cardiovascular development, angiogenesis.
Key words: Protein arginylation, ATE1, arginyltransferase.
Description of Research
Genomes of higher mammals encode an estimated 40,000 proteins, however the complexity of the functions performed by these proteins in vivo is at least an order of magnitude higher. This complexity is achieved in a large part by posttranslational modifications that modulate structure and functions of proteins after synthesis, thus increasing the variety of forms in which the proteins encoded by the same gene can exist in vivo. Evidence suggests that posttranslational modifications constitute a major mechanism for regulation of normal metabolism and disease in higher vertebrates. Discovery and understanding of new posttranslational modifications and uncovering the biological role of the poorly understood modifications constitutes a major emerging field.
The goal of our research is to investigate the physiological role of a previously uncharacterized posttranslational modification, protein arginylation. Knockout of the enzyme responsible for arginylation, ATE1, results embryonic lethality in mice and multiple defects related to heart development and blood vessel remodeling (angiogenesis). Our recent work showed that arginylation regulates many proteins involved in cytoskeleton, cell motility, signaling, and metabolism, and uncovered some mechanisms of this regulation.
Our current studies are focused on three major directions: (1) identification of the ATE1 protein targets and studying the effect of arginylation on their properties and functions; (2) studies of the structure and molecular properties of the mouse ATE1 enzymes; and (3) discovering the mechanisms and pathways that lead to the global physiological effects of protein arginylation.
Reena Rai -- Research Specialist,
Sougata Saha -- Postdoctoral Scholar,
Junling Wang -- Postdoctoral Scholar,
Fangliang Zhang -- Postdoctoral Scholar,
Satoshi Kurosaka -- Postdoctoral Scholar,
Adrian Leu -- Research Specialist,
Li Huang -- Research Specialist.
Wang, J., Han, X., Leu, N. A., Sterling, S., Kurosaka, S., Fina, M., Lee, V. M., Dong, D. W., Yates, J. R., Kashina, A. Protein arginylation targets alpha synuclein, facilitates normal brain health, and prevents neurodegeneration Sci Rep 7: 11323, 2017.Efimova, N., Korobova, F., Stankewich, M. C., Moberly, A. H., Stolz, D. B., Wang, J., Kashina, A., Ma, M., Svitkina, T. ßIII Spectrin Is Necessary for Formation of the Constricted Neck of Dendritic Spines and Regulation of Synaptic Activity in Neurons J Neurosci 37: 6442-6459, 2017.Rai, R., Zhang, F., Colavita, K., Leu, N. A., Kurosaka, S., Kumar, A., Birnbaum, M. D., Gyorffy, B., Dong, D. W., Shtutman, M., Kashina, A. Arginyltransferase suppresses cell tumorigenic potential and inversely correlates with metastases in human cancers Oncogene 35: 4058-4068, 2016.Leite, F. D. S., Kashina, A., Rassier, D. E. Posttranslational Arginylation Regulates Striated Muscle Function Exerc Sport Sci Rev 44: 98-103, 2016.Leite, F. S., Minozzo, F. C., Kalganov, A., Cornachione, A. S., Cheng, Y. S., Leu, N. A., Han, X., Saripalli, C., Yates, J. R., Granzier, H., Kashina, A. S., Rassier, D. E. Reduced passive force in skeletal muscles lacking protein arginylation Am J Physiol Cell Physiol 310: C127-C135, 2016.Zhang, F., Patel, D. M., Colavita, K., Rodionova, I., Buckley, B., Scott, D. A., Kumar, A., Shabalina, S. A., Saha, S., Chernov, M., Osterman, A. L., Kashina, A. Arginylation regulates purine nucleotide biosynthesis by enhancing the activity of phosphoribosyl pyrophosphate synthase Nat Commun 6: 7517, 2015.Leite, F. D. S., Minozzo, F. C., Trecarten, N., Han, X., Yates, J. R., Kashina, A., Rassier, D. E. Passive Force Analysis of Single Sarcomeres from Muscles Lacking Arginyl-tRNA-Protein Transferase (Ate1) Biophys J 108: 591A-591A, 2015.Saha, S., Wang, J., Kashina, A. S. High-Throughput Arginylation Assay in Microplate Format Methods Mol Biol 1337: 79-82, 2015.Wang, J., Kashina, A. S. Bacterial Expression and Purification of Recombinant Arginyltransferase (ATE1) and Arg-tRNA Synthetase (RRS) for Arginylation Assays Methods Mol Biol 1337: 67-71, 2015.Wang, J., Kashina, A. S. Assaying ATE1 Activity In Vitro Methods Mol Biol 1337: 73-77, 2015.