Miljan Simonovic

    Email Address: msimon5@uic.edu
    College: Medicine Department: Biochemistry and Molecular Genetics
    Title: Associate Professor
    Office: MBRB 1354 Phone: 312.996.0059
    Webpage: https://msimon5.people.uic.edu/Simonovic_Lab.html
    Participating in the Chancellor’s Undergraduate Research Awards program: Yes

    Research Interest:
    Our laboratory primarily studies mechanisms that ensure fidelity of mRNA translation. Misinsertion of amino acids into the growing polypeptide chain may cause protein misfolding or may yield proteins with different properties. These processes often cause the development of pathologic conditions in humans. Several projects are currently undergoing in the lab. The major project is focused on the mechanism of synthesis of the 21st amino acid, selenocysteine (Sec). Although found in only 25 human proteins, Sec is essential for survival. Erroneous replacement of Sec with serine or cysteine renders selenoenzymes inactive, thus, affecting critical cellular processes such as the removal of reactive oxygen species and thyroid hormone (in)activation. Four human enzymes catalyze selenocysteine synthesis in a process that is dependent on tRNASec and they evolved to bind the cognate tRNA with high affinity. This is in a striking contrast to 20 standard amino acids, which are mostly synthesized in their free form. The goal is to explain at the structural level the substrate specificity of the human Sec-synthetic enzymes. Besides the human system, we are interested in comparing human enzymes with archaeal orthologs. We have published several papers on this topic and this segment of our research program has been continuously funded by NIH since 2011. We are also studying the mechanism by which human elongation factors select their tRNA substrates. While the general elongation factor binds all tRNAs but selenocysteine tRNA, the selenocysteine-specific elongation factor binds only selenocysteine tRNA and rejects all other tRNAs. The elongation factors are one of the last checkpoints that prevent the misinsertion of amino acids. The goal of this project is to reveal a structural basis for the substrate specificity of both elongation factors. Most recently, we initiated studies about mechanisms by which errors in protein synthesis cause neurodegeneration.

    Minimum time commitment in hours per week: 12-18

    Qualifications of a Student:
    The candidate student must have a strong GPA with a major in basic biomedical sciences (e.g. chemistry, biochemistry, biology, biophysics, pre-med). The prior laboratory experience would be beneficial but it is not necessary.

    Brief Summary of what is expected from the student:
    A specific project will be assigned to every student. Besides learning basic molecular biology and biochemistry techniques, the student may be exposed to advanced methods routinely used in structural biology. The work will involve preparation of mutant enzymes and tRNA constructs, purification of recombinant proteins, in vitro transcription and tRNA purification, in vitro binding and activity assays, protein-tRNA complex purification, and macromolecular crystallization. Students who demonstrate strong work ethic and dedication will have the opportunity to learn how X-ray diffraction data are collected at the synchrotron source of X-rays in Argonne National Laboratory. Also, they may analyze the diffraction data and work on model building and structure refinement.

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