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Bibliography
Lab Web Page
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Sinisa Urban - Assistant Professor
Molecular Biology & Genetics
725 N. Wolfe Street
507 PCTB
BaltimoreMD21205
Office: 410-502-6247
surban@jhmi.edu |
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| Assistant: |
Cynthia Rogers |
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Cell membranes are sites of interface between the cell and the outside world, and constitute major sites of signaling. Membranes also form the front lines where deadly pathogens first contact human cells and initiate infection. Our main focus is a family of membrane-embedded enzymes, termed rhomboid proteases, which catalyze a biochemical reaction that cuts protein segments within the membrane. This cleavage liberates proteins from the membrane, either to activate signals rapidly, or to inactivate other targets. Because of its speed and versatility, this basic biochemical reaction has evolved to control many cellular processes in all forms of life, from diverse bacteria to humans. But how these enzymes achieve catalysis within the membrane, and their roles in all but a few organisms, remain unclear.
We study the biochemical principles governing how rhomboid enzymes catalyze reactions embedded within the membrane. We have reconstituted rhomboid activity with pure components, and are using a combination of membrane biochemistry, cell biology and chemical genetics to probe their mechanism. We have also focused on rhomboid function in deadly human pathogens, and discovered that rhomboid enzymes execute an array of essential functions: malaria and related parasites use their rhomboid enzymes to invade human cells, while a parasitic ameba uses its rhomboid in phagocytosis and immune evasion. Targeting rhomboid enzymes may be a way of treating multiple infectious diseases.
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| Relevant
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Urban, S. Making the cut: central roles of intramembrane proteolysis in pathogenic microorganisms (2009).
Nature Reviews Microbiology 7: 411-423 [cover article]
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Baxt, L.A., Baker R.P., Singh U., and S. Urban. An Entamoeba histolytica rhomboid protease with atypical specificity cleaves a surface lectin involved in
phagocytosis and immune evasion. (2008). Genes & Development 22(12): 1636-1646. [cover article]
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Urban S. and R.P. Baker.
In vivo analysis reveals substrate-gating mutants of a rhomboid intramembrane protease display increased activity in living cells. (2008).
Biological Chemistry 389: 1107-1115.
[cover article]
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Urban S. and Y. Shi. Core
principles of intramembrane proteolysis: comparison of rhomboid and site-2
family proteases. (2008). Current Opinion
in Structural Biology 18(4): 432-441.
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Baker, R.P., Young K., Feng L., Shi Y. and S. Urban. Enzymatic analysis of a rhomboid intramembrane proteases implicates transmembrane helix 5 as the lateral substrate gate. (2007). Proc. Natl. Acad. Sci. USA. 104 (20): 8257-8262. [cover article]
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Wu Z., Yan N.,Feng L., Oberstein A., Yan H., Baker R. P., Gu L., Jeffrey P.D.,Urban S., and Y. Shi. Structural analysis of a rhomboid family intramembrane protease reveals a gating mechanism for substrate entry. (2006). Nature Structural and Molecular Biology. 13 (12): 1084-1091.
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Urban S. Rhomboid proteins: conserved membrane proteases with divergent biological functions. (2006). Genes and Development. 20 (22): 3054-3068.
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Baker, R.P., Wijetilaka R, and S. Urban. Two Plasmodium rhomboid proteases preferentially cleave different adhesins implicated in all invasive stages of malaria. (2006). PLoS Pathogens. 10(2): e113.
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Brossier F., Jewett T., Sibley D. L., and S. Urban. A spatially-localized rhomboid protease cleaves cell surface adhesins essential for invasion by Toxoplasma. (2005). Proc. Natl. Acad. Sci. USA. <102(11):4146-4151.
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Urban S. and M. S. Wolfe. Reconstitution of intramembrane proteolysis in vitro reveals that pure rhomboid is sufficient for catalysis and specificity. (2005). Proc. Natl. Acad. Sci. USA. 102(6):1883-1888.
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Urban S. and M. Freeman. Substrate specificity of Rhomboid intramembrane proteases is governed by helix-breaking residues in the substrate transmembrane domain. (2003).Molecular Cell. 11: 1425-1434.
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Urban S., Schlieper D., and M. Freeman. Conservation of intramembrane proteolytic activity and substrate specificity in prokaryotic and eukaryotic Rhomboids (2002).Current Biology. 12: 1507-1512.
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Urban S., Lee J. R., and M. Freeman. A family of Rhomboid intramembrane proteases activates all Drosophila membrane-tethered EGF-like ligands (2002).EMBO Journal. 21: 4277-4286.
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Urban S., Lee J. R., and M. Freeman. Drosophila Rhomboid-1 defines a family of putative intramembrane serine proteases. (2001). Cell. 107 (2): 173-182.
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