Rubenstein, Peter - University of Iowa - Department of Biochemistry

个人简介

Education AB, Biochemistry, University of California, Berkeley MA, Biochemistry and Molecular Biology, Harvard University PhD, Biochemistry and Molecular Biology, Harvard University Post Doctoral Fellow, Biochemistry & Biophysics, University of California School of Medicine Post Doctoral Fellow, Biochemistry & Biophysics, University of California School of Medicine

研究领域

Our laboratory investigates the biochemistry of actin and the actin binding proteins that modulate its function within the cell. In particular, we are interested in the conformational changes in actin necessary for its polymerization, the forces that stabilize actin monomers within the actin filament, and the manner in which actin filament modulating proteins such as cofilin, Arp2/3 complex and profilin carry out their roles. Our approach is to use yeast actin and the yeast actin cytoskeleton as a model system. Based on hypotheses concerning actin function and actin dynamics, we make mutant actin constructs using site-directed mutagenesis, express the actin in yeast as the only actin in the cell, and determine phenotypes associated with the actin mutation such as altered growth rate, altered endocytosis, and altered actin deposition. We then purify the actin and determine its in vitro behavior using a series of biochemical and biophysical approaches such as electron microscopy and fluorescence spectroscopy. We then try to correlate the effects of the mutations we observe in vitro with the phenotypes associated with these mutations in vivo. With this basic system, we are currently focusing on two projects. We have shown that although the proteins are 90% identical, muscle and yeast actins display distinct differences in their kinetics and ability to interact with different actin binding proteins that can have a substantial effect on actin filament dynamics. To investigate the basis for these differences, we have made a set of yeast/muscle hybrid actins with one yeast half and one muscle half to try to determine which part of the actin is responsible for the behavioral differences seen between the two parent actins. Second, it has been found that six different actin mutations cause autosomal dominant hearing loss in humans. We have cloned each of these into yeast actin and are assessing the effects of these mutations in vivo and in vitro with the goal of gaining insight into altered actin interactions that might result in deafness.

近期论文

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Lee, C. Y., Lou, J., Wen, K. K., McKane, M., Eskin, S. G., Rubenstein, P. A., Chien, S., Ono, S., Zhu, C. & McIntire, L. V. (2016). Regulation of actin catch-slip bonds with a RhoA-formin module.. Scientific reports, 6, 35058. DOI: 10.1038/srep35058. Jepsen, L., Kruth, K. A. & Rubenstein, P. A. (2016). Molecular Effects of Deafness Mutations in Actin. Biophys J, 1110(2), 354a. DOI: 10.1016/j.bpj.2015.11.1909. Jepsen, L., Kruth, K. A., Rubenstein, P. A. & Sept, D. (2016). Two Deafness-Causing Actin Mutations (DFNA20/26) Have Allosteric Effects on the Actin Structure.. Biophysical journal, 111(2), 323-32. DOI: 10.1016/j.bpj.2016.06.012. Rubenstein, P. A., Wen, K. K. (2015). Mutant vascular actin is a TAAD misbehaving.. Proceedings of the National Academy of Sciences of the United States of America, 112(31), 9500-1. DOI: 10.1073/pnas.1512086112. Bai, F., Caster, H., Rubenstein, P., Dawson, J. & Kawai, M. (2014). Using baculovirus/insect cell expressed recombinant actin to study the molecular pathogenesis of HCM caused by actin mutation A331P. J Mol Cell Cardiol, 74, 64-75. DOI: 10.1016/j.yjmcc.2014.04.014. Yamashiro, S., Gokhin, D., Sui, Z., Bergeron, S., Rubenstein, P. & Fowler, V. (2014). Differential actin-regulatory activities of Tropomodulin1 and Tropomodulin3 with diverse tropomyosin and actin isoforms. J Biol Chem, 289(17), 11616-29. DOI: 10.1074/jbc.M114.555128. Rubenstein, P. A., Wen, K. K. (2014). Insights into the effects of disease-causing mutations in human actins. Cytoskeleton (Hoboken). DOI: 10.1002/cm.21169. Lee, C. Y., Lou, J., Wen, K. K., McKane, M., Eskin, S. G., Ono, S., Chien, S., Rubenstein, P. A., Zhu, C. & McIntire, L. V. (2013). Actin depolymerization under force is governed by lysine 113:glutamic acid 195-mediated catch-slip bonds. Proceedings of the National Academy of Sciences of the United States of America, 110(13), 5022-7. Johnston, J. J., Wen, K. K., Keppler-Noreuil, K., McKane, M., Maiers, J. L., Greiner, A. & Sapp, J. C. (2013). Functional Analysis of a De Novo ACTB Mutation in a Patient with Atypical Baraitser-Winter Syndrome. Human Mutation, doi: 10.1002/humu.22350.