Cellular Regulation by Reversible Macromolecular Assembly and Association

Biology is a dynamic process. Among the myriad array of reversible association reactions that constitute life, small molecules bind to proteins, proteins self-associate and bind to other proteins and nucleic acids and nucleic acids fold and bind to each other in elaborate processing, signaling and regulatory cascades. What is common to these processes is the physical chemistry that underlies these interactions. For example, electrostatic interactions mediate both the binding of proteins to DNA and the folding of RNA. Proteins that mimic the electrostatic character of DNA may competitively regulate DNA binding by other proteins. Our laboratory seeks answers to questions related to the structure – function relationships that govern macromolecular function by combining quantitative analysis with innovative approaches.

• The longest running programmatic theme of our laboratory is the study of the mechanisms by which proteins recognize and bind specific sequences of DNA. We have turned our attention to proteins involved in epigenetic regulation exploring the biophysics of an epigenetic regulatory methyl-CpG binding protein MeCP2 whose disruption is a cause of the neurological disorder Rett Syndrome.
• Our interest in RNA structure and folding has led us to explore the packaging and delivery of RNA therapeutics. We are using a biophysical method that quantitates the size and density of RNA delivery vehicles in support of their use as novel therapeutics.
• We have developed and utilize a high-throughput method to map protein-protein interactions using amino acid side chain oxidation by the hydroxyl radical to measure solvent accessibility as a tool for mapping the molecular interfaces of regulatory complexes and protein therapeutics.

Representative Publications

Wang, Q., Aleshintsev, A., Bolton, D., Zhuang, J., Brenowitz, M., Gupta R., Ca(II) and Zn(II) Cooperate To Modulate the Structure and Self-Assembly of S100A12 (2019) Biochemistry 58(17), 2269-2281

Warren, C., Matsui, T., Karp., J.M., Onikubo, T., Cahill, S., Brenowitz, M., Cowburn, D., Girvin, M., & Shechter, D. (2017) Histone Binding and Release by the Chaperone Nucleoplasmin is Controlled by Intramolecular Dynamics, Nature Communications, 8(1), 2215

Khrapunov, S., Tao, Y., Cheng, H., Padlan, C., Harris, R., Galanopoulou, A.S., Greally, J.M., Girvin, M.E., Brenowitz, M. (2016) MeCP2 Binding Cooperativity Inhibits DNA Modification-Specific Recognition Biochemistry. 55(31), 4275 - 85 Epub 2016 Jul 28

Leser, M., Pegan, J., El Makkaoui, M., Schlatterer, J.C., Khine, M., Law, M. & Brenowitz, M. (2015) Protein Footprinting by Pyrite Shrink-Wrap Laminate, Lab on a Chip 15(7), 1646 – 50

LoPiccolo, J., Kim, S.J., Shi, Y., Wu, B., Wu, H., Chait, B.T., Singer, R.H., Sali, A., Brenowitz, M., Bresnick, A.R., Backer, J.M. (2015) Assembly and Molecular Architecture of the Phosphoinositide 3- Kinase p85α Homodimer, J Biological Chemistry 290(51), 30,390-30,405