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Stephen Sprang, Professor & Director of CBSD

Office
Location: ISB 106A

Contact
Phone: 406-243-6028
Fax: 406-243-6024
Email: stephen.sprang@umontana.edu

Education

 B.S. in Biochemistry from California State University of Los Angeles in 1971

Ph.D. in Biochemistry from the University of Wisconsin, Madison in 1977

Postdoctoral studies with Robert Fletterick at the University of Alberta and the University of California at San Francisco, 1978-1983

Research Interests

We are among the research laboratories of the Center for Biomolecular Structure and Dynamics. We study the structural chemistry of cellular signal transduction - the protein machines that control the timeing and rate of processes such as cell division, gene transcription, electical conduction and mobilization of energy sources in cells.  Much of our work has been focused on  heterotrimeric G proteins, the ways that they are stimulated and repressed, and how they activate and inhibit regulatory enzymes in cells.  We employ X-ray crystallography, using the facilities of the Center, to study these processes at molecular and atomic detail.  In collaboration with Sandy Ross's laboratory, we use fluorescence specroscopy to observe conformational transitions in G proteins at single molecule resolution.

How do G proteins regulate effectors - how do effectors regulate G proteins?

When bound to GTP, G proteins regulate the activity of signaling molecules called effectors. Effectors may have reciprocal effects on G proteins, most commonly by accelerating GTP hydrolysis (thereby leading to dissociation of the G protein from its effector). Earlier work addressed the regulation of adenylyl cyclase by Gas,

and more recently, the mechanism by which Ga13 regulates G-protein dependent regulators of cytoskeleton formation. These remarkable effectors activate the small G protein, Rho.  At the same time, these effectors deactivate Ga13, resulting in tightly coupled cycles of G-protein activation and deactivation.

Selected Publications

Mou, TC, Masada, N, Cooper, DM, Sprang SR (2009) "Structural basis for inhibition of mammalian adenylyl cyclase by calcium" Biochemistry, 48, 3387-97 Free PMC Article

 

Chen, Z., Singer, WD,  Danesh, SM, Sternweis, PC, Sprang, SR (2008) "Recognition of the activated states of Galpha13 by the rgRGS domain of PDZRhoGEF, Structure, 16, 1532-43 Free PMC Article

 

Thomas, CJ, Tall, GG, Adhikari, A, Sprang, SR (2008) "Ric-8A catalyzes guanine nucleotide exchange on Galphai1 bound to the GPC/GoLoco exchange inhibitor AGS3" J. Biol. Chem., 283, 23150-60 Free PMC Article

 

Sprang, S (2007) “A Receptor Unlocked”, Nature, 450, 355-6

 

Sprang, SR, Chen, Z, Du, X (2007) "Structural basis of effector regulation and signal termination in heterotrimeric Galpha proteins", Adv. Protein. Chem.,74, 1-65

Field of Study

Structural Biology and Biochemistry: Biological Signal Transduction

Honors

Fellow of the American Association for the Advancement of Science, 2000

Publications

Coleman, D. E.,  Berghuis, A., Lee, E., Gilman, A. and Sprang, S. (1994). Structures of active conformations of Gia1 and the mechanism of GTP hydrolysis.  Science 265:1405-1412.

Naismith, J. H., Devine, T. Q., Brandhuber, B. J. and Sprang, S. R. (1995).  Crystallographic evidence for dimerization of unliganded tumor necrosis factor receptor.  Journal of Biological Chemistry 270:13303-13307.

Sutton, R. B., Davletov, B.A., Berghuis, A. M., Südhof, T. C. and Sprang, S. R. (1995).Structure of the first C2-domain of synaptotagmin I: A novel Ca2+/phospholipid binding fold.  Cell 80:929-938

Wall, M. A., Coleman, D. E., Lee, E., Iñiguez-Lluhi, J. A., Posner, B. A., Gilman, A. G. and Sprang, S. R. (1995).  The structure of the G protein heterotrimer Giab1g2. Cell 80:1047-105

Tesmer, J. J. G., Berman, D. M., Gilman, A. G. and Sprang, S. R. (1997).  Structure of RGS4 bound to AIF4-- activated Gia1: Stabilization of the transition state for GTP hydrolysis.  Cell 89:251-261

Sprang, S. R. (1997).  G Protein Mechanisms: Insights from structural analysis. Annual Review of Biochememistry 66:639-678.

Tesmer, J. J. G., Sunahara, R. K., Gilman, A. G. and Sprang, S. R. (1997).  Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsa•GTPgS. Science 278:1907-1916

Tesmer, J.J.G., Sunahara, R.K., Johnson, R.A., Gosselin G., Gilman, A.G., and Sprang, S.R (1999) Two metal ion catalysis in adenylyl cyclase revealed by its complexes with ATP analogs, Mg2+, Mn2+ and Zn2+. Science 285:756-760.

Xiao, T, Towb P., Wasserman, S.A. and Sprang, S.R. (1999) Three-Dimensional Structure of a Complex between the Death Domains of Pelle and Tube. Cell 99: 545-555.

Du, X, Black, G., Lecchi, P., Abramson, F. and Sprang, S.R. (2004) “Kinetic Isotope Effects in Ras-catalyzed GTP Hydrolysis: Evidence for a Loose Transition State” Proceedings of the National Academy of Sciences, USA 101, 8858-63

Mou, T.C., Gille, A., Fancy, DA, Seifert, R and Sprang, S.R.,  (2005) “Structural basis for the inhibition of mammalian adenylyl cyclase by 2’(3’)-O-(N-methylanthraniolyl)-guanosine 5’-triphosphate”  Journal of Biololgical Chemistry, 280:7253-61

 Chen, Z., Singer, W.D., Sternweis, P.C. and Sprang, S. R. “Structure of the p115rhoGEF rgRGS domain of-Ga1/i1 chimera complex suggests convergent evolution of a GTPase activator “ (2005), Nature Structural and Molecular Biology, 12:191-7

Sinha, S.C., Wetter, M., Schultz, Sprang, S. and Linder, J (2005) “Asymmetry in Homodimeric Adenylyl Cyclases: Structures of the Mycobacterium  tuberculosis Rv 1900c”  EMBO Journal, 24:663-73

Davis, T.,  Bonacci, T.M., Smrcka, AV. and Sprang, S.R. (2005) “Structural and Molecular Characterization  of a Preferred Protein Interaction Surface on G Protein bg Subunits” (2005) Biochemistry 44:10593-10604

 Ja, W.W., Adhikari, A., Austin, R.J., Sprang, S.R., Roberts, R.W.(2005) “A peptide core motif for binding to heterotrimeric G protein a subunits”  Journal of Biological Chemistry, 280:32057-32060

Mou, T-C, Gille, A., Suryanarayana, S.,Richter, M., Seifert, R. and Sprang, S.R.(2006) “Broad Specificity of Mammalian Adenylyl Cyclases for Interaction with 2’,3’-Substituted Purine-and Pyrimidine Nucleotide Inhibitors”  Molecular Pharmacology,70:878-886

Sinha, S.C. and Sprang, S. (2006) “Structures, mechanism, regulation and evolution of class III nucleotidyl cyclases” Reviews of Physiology, Biochemistry and Pharmacology 157:105-140

Sprang, S.R., Chen, Z and Du, X. (2007)“Structural basis of effector regulation and signal termination in heterotrimeric Ga proteins” Advances Prot. Chem. 74:1-65

Du, X., Ferguson, K., Gregory, R. and Sprang, S.R. (2008) “A method to determine 18O kinetic isotope effects in the hydrolysis of nucleotide triphosphates” Analytical Biochemistry 372:213-21