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Biophysics
Cell Biology and Physiology
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Protein Biochemistry
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Weber, David J., Ph.D.
Assistant Professor
Department of Biochemistry and Molecular Biology
E-mail: dweber@umaryland.edu


One project in our laboratory involves studies of the structure and function of S100B(ßß), a glial-derived protein from the brain. S100B(ßß) is a dimeric Ca2+-binding protein that is overproduced during gliosis in patients with Alzheimer disease, Down syndrome, and Aids related dementia. In addition, S100B(ßß) and/or other members of the S100 protein family (S100 , S100L, etc.) are found at high concentrations in several tumor cell lines including lung, bladder, kidney, cervix, breast, head and neck, larynx, lymph, and mouth. Thus, overproduction of S100 proteins may cause problems in the regulation of cell growth in these diseases. Presumably, the function of S100B(ßß) is related to its ability to bind a variety of target proteins in a Ca2+-dependent manner. One such target is the tumor suppressor protein, p53. For this protein, we have shown that upregulation of S100B abrogates p53 transcription activation by >50% in tumor cell lines and that S100B(ßß) binds and inhibits both the protein kinase C-dependent phosphorylation and the oligomerization of p53 in vitro. Therefore, the focus of our laboratory is to determine, at atomic resolution, the mechanism by which S100B can affect p53 transcription activation and promote uncontrolled cell growth. In this regard, we have determined the three-dimensional structure of apo-S100B(ßß) and the S100B(ßß)-Ca2+ complex using NMR spectroscopy, and the structure of the S100B(ßß)-Ca2+-p53 peptide complex is near completion. The structural studies of S100B(ßß) are imperative for the efficient design of biochemistry and molecular biology experiments that are also completed in our laboratory. In the future, knowledge about the structure and function of S100B(ßß) will be used to design molecules that inhibit S100B(ßß) from binding to p53. Perhaps one of these molecules will be practical as a drug for regulating uncontrolled cell growth in vivo. Similarly, structure/function studies are underway for two other members of the S100 protein family, S100a and S100L.

Rustandi, R.R., Baldisseri, D.M., Drohat, A.C., and Weber, D.J. Structural changes in the C-terminus of calcium-bound rat S100B upon binding a peptide derived from the C-terminal negative regulatory domain of p53 (1999) Protein Science, 8:1743-1751.



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