Sin Urban

Image of Dr. Sin Urban

Sin Urban

Professor
Additional Title: 
BCMB Admissions Director
Primary Appointment: 
Molecular Biology and Genetics
410-502-6247

725 N. Wolfe Street
507 PCTB
Baltimore MD 21205

Research topic: 

Biophysics, 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, that cut protein segments within the membrane. This cleavage liberates proteins from the membrane, either to activate signals rapidly, or to inactivate selected targets. Because of its 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 biophysics, 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.

BCMB students currently in the lab:
Selected Publications: 

Urban S. Cartography of intramembrane proteolysis. (2016). Cell, 167(7):1898.

Cho S., Dickey S.W., and S. Urban. Crystal structures and inhibition kinetics reveal a two-stage catalytic mechanism with drug design implications for rhomboid proteolysis. (2016). Molecular Cell, 61(3): 329-340.

Baker R.P. and S. Urban. Cytosolic extensions directly regulate a rhomboid protease by modulating substrate gating. (2015). Nature 523(7558): 101-105.  (DOI: 10.1038/nature14357) 

Urban S., Moin S.M. A subset of membrane-altering agents and ?-secretase modulators provoke nonsubstrate cleavage by rhomboid proteases. (2014). Cell Reports 8(5):1241-1247. doi: 10.1016/j.celrep.2014.07.039.

Dickey S.W., Baker R.P., Cho S., and  S. Urban. Proteolysis inside the membrane is a rate-governed reaction not driven by substrate affinity. (2013). Cell, 155(6): 1270-1281.

Moin S. and S. Urban. Membrane immersion allows rhomboid proteases to achieve specificity by reading transmembrane segment dynamics. (2012). eLife, 1: e00173. (DOI 10.7554/eLife.00173)

Baker R.P. and S. Urban. Architectural and thermodynamic principles underlying intramembrane protease function. (2012). Nature Chemical Biology 8(9): 759-768. (DOI 10.1038/nchembio.1021)

Urban, S. and Dickey S.W. The rhomboid protease family; a decade of progress on function and mechanism. (2011). Genome Biology, 12(10): 231-41.

Urban, S. Making the cut: central roles of intramembrane proteolysis in pathogenic microorganisms (2009). Nature Reviews Microbiology 7: 411-423 [cover article]

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]

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]

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.

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.

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

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.

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.

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.