Dr. Joachim Weber

Principal Research Interests

• ATP Synthase – The World's Smallest Rotary Motor
• Mutational Analysis of Enzymatic Function
• Biophysical Chemistry

ATP is the fuel for energy-requiring processes in all organisms.  Every day the human body produces approximately its own weight in ATP.  The enzyme ATP synthase is responsible for the bulk of ATP synthesis.  It uses a transmembrane proton gradient to synthesize ATP from ADP and inorganic phosphate, and it hydrolyses ATP to transport protons across the membrane.  ATP synthesis/hydrolysis and proton translocation are tightly coupled by a unique mechanism, subunit rotation, making ATP synthase a very efficient rotary nanomotor.  The long-term goal of Dr. Weber's research is to understand the mechanism of ATP synthase in molecular detail.



Dr. Weber's current work focuses on the question how ATP binding and hydrolysis in the catalytic site drive subunit rotation, using a variety of approaches. The applied techniques range from molecular biology (site-directed mutagenesis) to biochemistry (protein chemistry, enzyme kinetics) to biophysical chemistry (fluorescence spectroscopy) and molecular modeling. Molecular dynamics simulations and torque measurements by single-molecule analysis are performed in collaboration with other laboratories. Noteworthy recent results of this research were (a) the identification of the catalytically-active nucleotide binding site, (b) the functional analysis of a unique hydrogen-bonding network between two subunits of the enzyme, and (c) further insight into the coupling mechanism between catalysis and rotation.

Research in Dr. Weber's lab is supported by the NIH.

Representative Publications

• "Escherichia coli ATP synthase with a b/delta fusion protein allows analysis of the functions of the individual b subunits", Gajadeera, C.S.; Weber, J., J. Biol. Chem. 2013, 288, in press.
• "P-glycoprotein is fully active after multiple tryptophan substitutions", Swartz, D.J.; Weber, J.; Urbatsch, I.L., Biochim. Biophys. Acta 2013, 1828, 1159-1168.
• "The beta subunit loop that couples catalysis and rotation in ATP synthase has a critical length", Mnatsakanyan, N.; Kemboi, S.K.; Salas, J.; Weber, J., J. Biol. Chem. 2011, 286, 29788-29796.
• "Toward the ATP synthase mechanism", Weber, J., Nat. Chem. Biol. 2010, 6, 794-795.
• "ATP synthase with its gamma subunit reduced to the N-terminal helix can still catalyze ATP synthesis", Mnatsakanyan, N.; Hook, J.A.; Quisenberry, L.; Weber, J., J. Biol. Chem. 2009, 284, 26519-26525.
• "The role of the betaDELSEED-loop of ATP synthase", Mnatsakanyan, N.; Krishnakumar, A.M.; Suzuki, T.; Weber, J., J. Biol. Chem. 2009, 284, 11336-11345.
• "An essential hydrogen-bonding network at the beta(DP)/alpha(DP) interface of ATP synthase", Mao, H.Z.; Abraham, C.G.; Krishnakumar, A.M.; Weber, J. J. Biol. Chem., 2008, 283, 24781-24788.
• "Identification of the beta(TP) site in the x-ray structure of F1-ATPase as the high-affinity catalytic site", Mao, H.Z.; Weber, J. Proc. Natl. Acad. Sci. U. S. A.2007, 104, 18478-18483.
• "ATP synthase - the structure of the stator stalk", Weber, J. Trends Biochem. Sci. 2007, 32, 53-56.
• "Does F1-ATPase have a catalytic site that preferentially binds MgADP?", Mao, H.Z.; Gray, W.D.; Weber, J. FEBS Lett. 2006, 580, 4131-4135.
• "ATP synthase: subunit-subunit interactions in the stator stalk", Weber, J. Biochim. Biophys. Acta2006, 1757, 1162-1170.
• "Structural characterization of the interaction of the delta and alpha subunits of the Escherichia coli F1F0-ATP synthase by NMR spectroscopy", Wilkens, S.; Borchardt, D.; Weber, J.; Senior, A.E. Biochemistry2005, 44, 11786-11794.
• "Happy motoring with ATP synthase", Senior, A.E.; Weber, J. Nature Struct. Mol. Biol.2004, 11, 110-112.
• "Fluorescent probes applied to catalytic cooperativity in ATP synthase", Weber, J.; Senior, A.E. Methods Enzymol.2004, 380, 132-152.
• "Quantitative determination of direct binding of b subunit to F1 in Escherichia coli F1F0-ATP synthase", Weber, J.; Wilke-Mounts, S.; Nadanaciva, S.; Senior, A.E. J. Biol. Chem.2004, 279, 11253-11258.