msimon5@uic.edu
|
|
Miljan Simonovic, Ph. D. Assistant Professor
B.S., Biochemistry, Summa Cum Laude, 1995
Faculty of Chemistry
University of Belgrade, Belgrade, Serbia
(Advisor: Prof. Vukic Soskic)
Ph.D., Biochemistry, 2002
University of Illinois at Chicago
(Advisor: Prof. Peter G.W. Gettins)
Postdoctoral training, Prof. Thomas A. Steitz
Department of Molecular Biophysics and Biochemistry
Yale University, 2003-2008
|
|
The main research interest is to study both structure and function of macromolecular complexes at atomic resolution by using primarily the methods of X-ray crystallography and general biochemistry. Currently, two main areas are being pursued in the laboratory.
1. Structural studies of the spectrin-based cytoskeleton
 
The long-term interest is to study interactions between spectrin and its ligands that are located at the membrane-cytosol interface, and to explain at the structural level how spectrins stabilize the membrane structure. The spectrin-based cytoskeleton is present in every human cell and at its core is the high-affinity ankyrin-spectrin complex that tethers integral membrane proteins to actin filaments. Besides being attached to the cell membrane, spectrins are found in other membrane-containing structures such as lysozomes and Golgi, and have been implicated to play an important role in protein sorting and trafficking. The goal is to decipher how distinct and yet structurally homologous spectrin repeats recognize different proteins and to provide a structural understanding of the mechanism by which specific binding events are transmitted along the spectrin filament. Another part of the study is focused on providing a complete model of the full-length ankyrin, which is the major binding partner of spectrin.
2. The mechanism of selenocysteine formation in humans
 
Selenocysteine, the 21st genetically encoded amino acid, is the major metabolic product of the essential dietary trace element selenium. It is found in 25 human proteins and among them are the enzymes that are responsible for the thyroid hormone activation as well as for the removal of reactive oxidative species. Although it is essential for survival, selenocysteine is not found in free form presumably due to its toxicity. Also, its incorporation into growing polypeptide is encoded by a UGA codon, which is a translational stop signal under the normal circumstances. Thus, the tRNA-dependent mechanism of selenocysteine formation as well as the mechanism responsible for decoding of the selenocysteine-inserting UGA has evolved in all selenocysteine-containing organisms. At least five human enzymes are responsible for selenocysteine synthesis and all have high specificity both for tRNASec and for a distinct aminoacyl group that is covalently attached to it. The goal of this project is to determine the molecular mechanism of formation of the selenocysteinyl moiety as well as the mechanism of its co-translational incorporation into nascent polypeptide.
Publications:
1. Palioura S, Sherrer RL, Steitz TA, Söll D, Simonovic M (2009) Human SepSecS-tRNASec complex reveals the mechanism of selenocysteine formation, Science, 325, 321-325 (Evaluated for Faculty of 1000).
2. Simonovic M and Steitz TA (2009) A structural view onto the ribosome-catalyzed peptide bond synthesis, Biochim. Biophys. Acta, doi:10.1016/j.bbagrm.2009.06.006
3. Stabach PR, Simonovic I, Ranieri MA, Aboodi, MS, Steitz TA, Simonovic M*, Morrow JS (2009) The structure of the ankyrin-binding site of b-spectrin reveals how tandem spectrin-repeats generate unique ligand-binding properties, Blood, 113, 5377-5384 (* - Corresponding author).
4. Simonovic M and Steitz TA (2008) Peptidyl-CCA deacylation on the ribosome promoted by induced fit and the O3’-hydroxyl group of A76 of the unacylated A-site tRNA, RNA, 14, 2372-2378.
5.
Simonovic M and Steitz TA (2008) Cross-crystal averaging reveals that the peptidyl-transferase center is the same in the 70S ribosome and 50S subunit, Proc. Natl. Acad. Sci., 105, 500-505.
6. Simonovic M, Zhang Z, Cianci CD, Steitz TA, Morrow JS (2006) Structure of the calmodulin aII-spectrin complex provides insight into the regulation of cell plasticity. J. Biol. Chem., 281, 34333-34340.
7. Simonovic M, Volz K, Salvessen G, Gettins PG (2005) Lack of involvement of strand s1'A of the viral serpin CrmA in anti-apoptotic or caspase-inhibitory functions. Arch. Biophys. Biochem, 440, 1-9.
8. Viswanathan VK, Koutsouris A, Lukic S, Pilkinton M, Simonovic I, Simonovic M, Hecht G. (2004) Comparative analysis of EspF from enteropathogenic and enterohemorrhagic Escherichia coli in alteration of epithelial barrier function. Infection and Immunity, 72, 3218-3227..
9. Dementiev A, Simonovic M, Volz K, Gettins PG (2003) Canonical inhibitor-like interactions explain reactivity of a1-proteinase inhibitor Pittsburgh and antithrombin with proteinases. J. Biol. Chem., 278, 37881-37887.
10. Gettins PG, Simonovic M, Volz K, (2002) Pigment epithelium-derived factor (PEDF), a serpin with potent anti-angiogenic and neurite outgrowth-promoting properties. Biol. Chem., 383, 1677-1682.
11. Simonovic M and Volz K, (2002) Atomic resolution structure of a succinimide intermediate in E. coli CheY. J. Mol. Biol., 322, 663-667.
12. Simonovic M and Volz K, (2001) A distinct meta-active conformation in the 1.1 Å resolution structure of wild type, apo-CheY. J. Biol. Chem., 276,28637-28640. (Evaluated for Faculty of 1000).
13. Simonovic M, Gettins PG, Volz K, (2001) Crystal structure of human PEDF, a potent anti-angiogenic and neurite growth-promoting factor. Proc. Natl. Acad. Sci., 98, 11131-11135.
14. Simonovic M, Dolmer K, Huang W, Strickland DK, Volz K, Gettins PG, (2001) X-ray structure and calcium affinity of ligand-binding repeat CR7 from LRP. Comparison with related domains from LRP and LDL receptor. Biochemistry, 40, 15127-15134.
15. Simonovic M, Gettins PG, Volz K, (2000) Crystallization and preliminary X-ray diffraction analysis of a recombinant cysteine-free mutant of CrmA. Acta Cryst. D,56, 1440-1442.
16. Simonovic M, Gettins PG, Volz K, (2000) Crystal structure of viral serpin crmA provides insights into its mechanism of cysteine proteinase inhibition. Protein Sci., 9, 1423-1427.
17. Ma J, Simonovic M, Qian R, Colley KJ, (1999) Sialyltransferase isoforms are phosphorylated in the cis-medial Golgi on serine and threonine residues in their luminal sequences. J. Biol. Chem., 274, 8046-8052.
18. Simonovic M, Soskic V, Joksimovic J, (1999) Purification of Gai1,2 subunit from bovine brain by affinity chromatography. Yug. Med. Bioch., 17, 385-390.
19. Simonovic M, Soskic V, Joksimovic J, (1998) Quantification of human dopamine D2S receptor interactions with Gai1,2- and Gao-proteins. Neurochemistry Int., 33, 271-275.
Honors and Awards:
2003: The Jane Coffin Childs Postdoctoral Fellowship, Yale University
2001: The Dean’s Scholarship, University of Illinois at Chicago
1999: The University Fellowship, University of Illinois at Chicago
1996: The Serbian Chemical Society Award
1996: The Department of Biochemistry Award, University of Belgrade
|
