Sinisa Urban

Academic Titles: 
Professor
410-502-6247

725 N. Wolfe Street

Baltimore, MD 21205

Research Interest: 
Biochemistry, cell and chemical biology of intra-membrane proteases in cell signaling and microbial pathogenesis

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-immersed 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 immersed 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.

Lab Members:
Name Classificationsort descending Email
Sangwoo Cho Research Associate scho59@jhmi.edu
Cynthia Rogers MBG Administrative Staff crogers4@jhmi.edu
Rosanna Baker Research Associate rbaker39@jhmi.edu
Alex Kreutzberger Postdoctoral Fellow
Ming Ji Postdoctoral Fellow mji9@jhmi.edu
McKinzie Garrison Graduate Student
Shiv Gandhi Graduate Student shiv.gandhi@jhmi.edu
Selected Publications:
Urban S. (2016) Cartography of intramembrane proteolysis. Cell 167(7):1898. [ link ] [ pdf ]
Cho S, Dickey SW, Urban S. (2016) Crystal Structures and Inhibition Kinetics Reveal a Two-Stage Catalytic Mechanism with Drug Design Implications for Rhomboid Proteolysis. Molecular Cell 61(3):329-40. [ link ] [ pdf ]
Baker RP, Urban S. (2015) Cytosolic extensions directly regulate a rhomboid protease by modulating substrate gating. Nature 523, 101–105. [ link ]
Urban S, Moin SM. (2014) A subset of membrane-altering agents and gamma-secretase modulators provoke nonsubstrate cleavage by rhomboid proteases. Cell Reports 8, 1241–1247. [ link ]
Dickey WS, Baker RP, Cho S, Urban S. (2013) Proteolysis inside the membrane is a rate-governed reaction not driven by substrate affinity. Cell 155, 1270–1281. [ pdf ]
Moin SM, Urban S. (2012) Membrane immersion allows rhomboid proteases to achieve specificity by reading transmembrane segment dynamics. Elife 1, e00173. [ link ]
Baker RP, Urban S. (2012) Architectural and thermodynamic principles underlying intramembrane protease function. Nature Chemical Biology. 8, 759–768. [ link ]
Urban S, Dickey SW. (2011) The rhomboid protease family: a decade of progress on function and mechanism. Genome Biology 12, 231. [ link ]
Urban S. (2009) Making the cut: central roles of intramembrane proteolysis in pathogenic microorganisms. Nature Reviews Microbiology 7, 411–423. [ link ]
Baxt LA, Baker RP, Singh U, Urban S. (2008) An Entamoeba histolytica rhomboid protease with atypical specificity cleaves a surface lectin involved in phagocytosis and immune evasion. Genes & Development 22, 1636–1646. [ link ]
Baker RP, Young K, Feng L, Shi Y, Urban S. (2007) Enzymatic analysis of a rhomboid intramembrane protease implicates transmembrane helix 5 as the lateral substrate gate. Proceedings of the National Academy of Sciences USA 104, 8257–8262. [ link ]
Baker RP, Wijetilaka R, Urban S. (2006) Two Plasmodium rhomboid proteases preferentially cleave different adhesins implicated in all invasive stages of malaria. PLoS Pathogens 2, e113. [ link ]
Brossier F, Jewett TJ, Sibley LD, Urban S. (2005) A spatially localized rhomboid protease cleaves cell surface adhesins essential for invasion by Toxoplasma. Proceedings of the National Academy of Sciences USA 102, 4146–4151. [ link ]
Urban S, Wolfe MS. (2005) Reconstitution of intramembrane proteolysis in vitro reveals that pure rhomboid is sufficient for catalysis and specificity. Proceedings of the National Academy of Sciences USA 102, 1883–1888. [ link ]
Urban S, Freeman M. (2003) Substrate specificity of rhomboid intramembrane proteases is governed by helix-breaking residues in the substrate transmembrane domain. Molecular Cell 11, 1425–1434. [ link ]
Urban S, Lee JR, Freeman M. (2002) A family of Rhomboid intramembrane proteases activates all Drosophila membrane-tethered EGF ligands. EMBO Journal 21, 4277–4286. [ link ]
Urban S, Lee JR, Freeman M. (2001) Drosophila rhomboid-1 defines a family of putative intramembrane serine proteases. Cell 107, 173–182. [ link ]