Penn Medicine
   
 

Yale Goldman, M.D., Ph.D.

 

Contact Information

Department of Physiology
School of Medicine
D700 Richards Building
Philadelphia, PA 19104-6083
Phone: (215) 898-4017
Fax: (215) 898-2653
E-mail: goldmany@mail.med.upenn.edu
Position: Professor

Research Interests

Motor Proteins

Muscle is a prototype biological energy transducer that can be understood at a particularly fine level of detail. The nearly crystalline organization of actin and myosin within a fiber allows the reaction sequence to be probed by biophysical, physiological, chemical and structural studies. A cyclic interaction between actin and myosin transforms free energy of splitting ATP into motion and mechanical work. Modified forms of this mechanism power other cell biological motions such as targeted vesicle transport and cell division. We are using novel biophysical techniques, including laser photolysis of 'caged molecules', bifunctional fluorescent probes and single molecule fluorescence polarization to map the real-time domain motions of the motor proteins. We are relating the structural changes to the enzymatic reactions and mechanical steps of the energy transduction mechanism.

Ribosomal Elongation Factors

Although the ribosome has been studied extensively since the unraveling of the genetic code, how it accomplishes the enormous fidelity of translating messenger RNA codons into amino acid sequences during protein biosynthesis is not understood. The ribosome is a motor translocating along the mRNA exactly 3 bases per elongation cycle. Energy from splitting GTP by G-protein elongation factors (EFs) is transformed into translational accuracy and maintenance of the reading frame. Codon-anticodon base pairing between mRNA and tRNA 'reads' the code, but EF-Tu 'proofreads' it. EF-G may be the motor. Powerful techniques developed for studies on motor proteins, including single molecule fluorescence and optical traps, may be applied to understand the structural biology, energetics and function of EFs in their working environment.

Representative Publications

  1. Goldman YE, Hibberd MG, Trentham DR. Initiation of active contraction by photogeneration of adenosine-5'-trisphosphate in rabbit psoas muscle fibres. J Physiol (Lond) 345:605-624, 1984. [Abstract]
  2. Hibberd MG, Dantzig JA, Trentham DR, Goldman YE. Phosphate release and force generation to skeletal muscle fibers. Science 228:1317-1319, 1985. [Abstract]
  3. Goldman YE. Measurement of sarcomere shortening in skinned fibers from frog muscle by white light diffraction. Biophys J 52:57-68, 1987. [Abstract]
  4. Walker JW, Somlyo AV, Goldman YE, Somlyo AP, Trentham DR. Kinetics of smooth and skeletal muscle activation by laser pulse photolysis of caged inositol 1,4,5-trisphosphate. Nature 327: 249-252, 1987. [Abstract]
  5. Goldman YE. Kinetics of the actomyosin ATPase in muscle fibers. [Review] Annual Review of Physiology. 49:637-54, 1987. [Abstract]
  6. Higuchi H, Goldman YE. Sliding distance between actin and myosin filaments per ATP molecule hydrolyzed in skinned muscle fibres. Nature 352:352-354, 1991. [Abstract]
  7. Tanner JW, Thomas DD, Goldman YE. Transients in orientation of a fluorescent cross-bridge probe following photolysis in caged nucleotides in skeletal muscle fibres. J Mol Biol 223:185-203, 1992. [Abstract]
  8. Hirose K, Franzini-Armstrong C, Goldman YE, Murray JM. Shape changes in the myosin molecule accompanying activation: analysis of cross-sectional electron micrographs from fibers ultra-rapidly frozen following activation by photolysis of caged ATP. J Cell Biol 127:763-778, 1994. [Abstract]
  9. Higuchi H, Yanagida T, Goldman YE. Compliance of thin filaments in skinned fibers of rabbit skeletal muscle. Biophys J 69:1000-1010, 1994. [Abstract]
  10. Irving M, Allen TStC, Sabido-David C, Craik JS, Brandmeier B, Kendick-Jones J, Corrie JET, Trentham DR, Goldman YE. The light chain region of myosin tilts during step length changes and active force generation in skeletal muscle. Nature 375:688-691, 1995. [Abstract]
  11. Allen TStC, Ling N, Irving M, Goldman YE. Orientation changes in myosin regulatory light chains following photorelease of ATP in skinned muscle fibers. Biophys. J. 70:1847-1862, 1996. [Abstract]
  12. Lenart, T.L., Murray, J.M., Franzini-Armstrong, C. and Goldman, Y.E. Structure and periodicities of cross-bridges in relaxation, rigor and during contractions initiated by photolysis of caged Ca2+. Biophys. J. 71:2289-2306, 1996. [Abstract]
  13. Berger CL, Craik JS, Trentham DR, Corrie JET, Goldman YE. Fluorescence polarization transients from skeletal muscle fibers labeled with rhodamine isomers at SH-1 of the myosin heavy chain. Biophys. J. 71:3330-3343, 1996. [Abstract]
  14. Goldman, Y.E. Wag the Tail: Structural Dynamics of Actomyosin. Cell,93:1-4.1998. [Abstract]
  15. Hopkins, S.C., Sabido-David, C., Corrie, J.E.T., Irving, M., and Goldman, Y.E. Fluorescence Polarization Transients from Rhodamine Isomers on the Myosin Regulatory Light Chain in Skeletal Muscle Fibers. Biophys. J., 74:3093-3110.1998. [Abstract]
  16. Dantzig, J.A., Higuchi, H., and Goldman, Y.E.Studies of Molecular Motors using Caged Compounds. Methods in Enzymology, 291:307-334.1998. [Abstract]
  17. Dale, R.E., Hopkins, S.C., van der Heide, U.A., Marszalek, T., Irving, M., and Goldman, Y.E.Model-Independent Analysis of the Orientation of Fluorescent Probes with Restricted Mobility in Muscle Fibers. Biophys. J.,76:1606-1618.1999. [Abstract]
  18. Taylor, K.A., Schmitz, H., Reedy, M.C., Goldman, Y.E., Franzini-Armstrong, C., Sasaki, H., Tregear, R.T., Poole, K., Lucaveche, C., Edwards, R.J., Chen, L.F., Winkler, H., and Reedy, M.K.Tomographic 3-D Reconstruction of Quick-Frozen, Ca2+-Activated Contracting Insect Flight Muscle. Cell, 99:421-431.1999. [Abstract]
  19. Rome, L.C., Cook, C., Syme, D.A., Ashley-Ross, M., Klimov, A., and Goldman, Y.E. Trading Force For Speed:Why Superfast Crossbridge Kinetics Leads to Super Low Forces. Proc. Nat. Acad. Sci., 96:5826-5831.1999 [Abstract]
  20. Corrie, J.E.T., Brandmeier, B.D., Ferguson, R.E., Trentham, D.R., Kendrick-Jones, J., Hopkins, S.C., van der Heide, U.A., Goldman, Y.E., Sabido-David, C., Dale, R.E., Criddle, S., and Irving, M. Dynamic Measurement of Myosin Light-Chain-Domain Tilt and Twist in Muscle Contraction. Nature, 400:425-430.1999. [Abstract]
  21. Van der Heide, U.A., Hopkins, S.C., and Goldman, Y.E.A Maximun Entropy Analysis of Protein Orientations Using Fluorescence Polarization Data from Multiple Probes. Biophys. J., 78:2138-2150.2000. [Abstract]
  22. Forkey JN, Quinlan ME, Goldman YE. Protein structural dynamics by single-molecule fluorescence polarization. Prog. Biophys. Mol. Biol., 74:1-35. 2000.
  23. Cheung A, Dantzig JA, Hollingworth S, Baylor SM, Goldman YE, Mitchison TJ, Straight AF. A small-molecule inhibitor of skeletal muscle myosin II. Nat. Cell. Biol., 4:83-8. 2002. [Abstract]
  24. Hopkins SC, Sabido-David C, van der Heide UA, Ferguson RE, Brandmeier BD, Dale RE, Kendrick-Jones J, Corrie JE, Trentham DR, Irving M, Goldman YE. Orientation changes of the myosin light chain domain during filament sliding in active and rigor muscle. J. Mol. Biol., 318:1275-91. 2002. [Abstract]
  25. Bell MG, Dale RE, van der Heide UA, Goldman YE. Polarized fluorescence depletion reports orientation distribution and rotational dynamics of muscle cross-bridges. Biophys. J., 83:1050-73. 2002. [Abstract]
  26. Forkey JN, Quinlan ME, Alexander Shaw M, Corrie JE, Goldman YE. Three-dimensional structural dynamics of myosin V by single-molecule fluorescence polarization. Nature, 422:399-404. 2003. [Abstract]
  27. Shaw MA, Ostap EM, Goldman YE. Mechanism of inhibition of skeletal muscle actomyosin by N-Benzyl-p-toluenesulfonamide. Biochemistry. 42:6128-35. 2003. [Abstract]
  28. Yildiz A, Forkey JN, McKinney SA, Ha T, Goldman YE, Selvin PR. Myosin V walks hand-over-hand: single fluorophore imaging with 1.5-nm localization. Science, 300:2061-5. 2003. [Abstract]
  29. Vanzi F, Vladimirov S, Knudsen CR, Cooperman BS, Goldman YE. Protein Synthesis by Single Ribosomes. RNA. 9:1174-9. 2003. [Abstract]
  30. Tregear RT, Reedy MC, Goldman YE, Taylor KA, Winkler H, Franzini-Armstrong C, Sasaki H, Lucaveche C, Reedy MK. Cross-bridge Number, Position and Angle in Target Zones of Isometrically Active Insect Flight Muscle. Biophys J. 86:3009-19. 2004. [Abstract]
  31. Liu, J., Reedy, M.C., Goldman, Y.E., Franzini-Armstrong, C., Sasaki, H., Tregear, R.T., Lucaveche, C., Winkler, H., Baumann, B.A.J., Squire, J.M., Irving, T.C., Reedy, M.K., and Taylor, K.A. Electron Tomography of Fast Frozen, Stretched Rigor Fibers Reveals Elastic Distortions in the Myosin Crossbridges. J. Struct. Biol., 147:247-258. 2004. [Abstract]
  32. Rosenberg, S.A., Quinlan, M.E., Forkey, J.N., and Goldman Y.E. Rotational Motions of Macromolecules by Single Molecule Fluorescence Microscopy. Acc. Chem. Res., 38:583-593. 2005. [Abstract]
  33. Forkey, J.N., Quinlan, M.E., and Goldman, Y.E. Measurement of Single Macromolecule Orientation by Total Internal Reflection Fluorescence Polarization Microscopy. Biophys. J., 89:1261-1271. 2005. [Abstract]
  34. Quinlan, M.E., Forkey, J.N., and Goldman, Y.E. Orientation of the Myosin Light Chain Region by Single and Multiple Molecule Total Internal Reflection Fluorescence Polarization Microscopy. Biophys. J., 89:1132-1142. 2005. [Abstract]
  35. Vanzi, F., Takagi, Y., Shuman, H., 32-Cooperman, B.S., and Goldman, Y.E. Mechanical Studies of Single Ribosome/mRNA Complexes. Biophys. J., 89:1909-1919. 2005. [Abstract]
  36. Beausang, J.F., Y. Sun, M.E. Quinlan, J.N. Forkey, and Y.E. Goldman. 2007. Single Molecule Fluorescence Polarization via Polarized Total Internal Reflection Fluorescent Microscopy. In Laboratory Manual for Single Molecule Studies. Sialiano I, editor. Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. [Appendix]
  37. Sun Y, Schroeder HW 3rd, Beausang JF, Homma K, Ikebe M, and Goldman YE. Myosin VI Walks "Wiggly" on Actin with Large and Variable Tilting. Mol Cell. 28:954-964. 2007. [Abstract] [PNAS Letter]
  38. Ross JL, Shuman H, Holzbaur EL, and Goldman YE. Kinesin and Dynein-Dynactin at Intersecting Microtubules: Motor Density Affects Dynein Function. Biophys J. 94:3115-3125. 2008. [Abstract]
  39. Dixit R, Ross JL, Goldman YE, Holzbaur EL. Differential Regulation of Dynein and Kinesin Motor Proteins by
    Tau. Science. 319:1086-1089. 2008. [Abstract]
  40. Beausang, J.F., Schroeder, H.W. 3rd, Nelson, P.C., and Goldman, Y.E. Twirling of Actin by Myosins II and V Observed via Polarized TIRF in a Modified Gliding Assay. Biophys J. 95:5820-5831. 2008. [Abstract]
  41. Dixit R, Barnett B, Lazarus JE, Tokito M, Goldman YE, Holzbaur EL. Microtubule Plus-End Tracking by CLIP-170 Requires EB1. Proc. Nat. Acad. Sci. 106:492-497. 2009. [Abstract]
  42. Arsenault ME, Sun Y, Bau HH, Goldman YE. Using electrical and optical tweezers to facilitate studies of molecular motors. Phys Chem Chem Phys. 11:4834-4839. 2009. [Abstract]
  43. Sun Y, McKenna JD, Murray JM, Ostap EM, Goldman YE. Parallax: high accuracy three-dimensional single molecule tracking using split images. Nano Lett. 9:2676-2682. 2009. [Abstract]
  44. Park, J.H., Sun, Y., Goldman, Y.E., and Composto, R.J. Self-Assembled Charged Hydrogels Control the Alignment of Filamentous Actin. Soft Matter, In Press, 2010. [Abstract]
  45. Sun, Y., Sato, O., Ruhnow, F., Arsenault, M.E., Ikebe, M. and Goldman, Y.E. Single Molecule Stepping and Structural Dynamics of Myosin X. Nat. Struct. and Mol., Biol. In Press, 2010. [Abstract]

 
 
Pennsylvania Muscle Institute
Perelman School of Medicine University of Pennsylvania
Director: E. Michael Ostap, Ph.D.
700A Clinical Research Building Philadelphia, PA 19104-6085 Phone: (215) 573-9758 Fax: (215) 898-2653