Associate Professor, Department of Physiology & Biophysics
Biological motor proteins use the energy from ATP hydrolysis to generate force and movement in the cells
We are interested in elucidating the structural basis of the mechanism of action of molecular motors. There are three superfamilies of molecular motors that produce linear forces and movement along cytoskeletal tracks, the myosins, the kinesins and the dyneins. These motors use the energy of ATP hydrolysis to move along cytoskeletal filaments. Myosins move along actin filaments while kinesin and dyneins move along microtubules.Currently our main focus is on the kinesin superfamily.
The kinesin superfamily plays essential roles in intracellular motile processes such as organelle transport and cell division. Absence or malfunction of kinesins have been associated with several human diseases such as motor neuron disease, Alzheimer's disease, retinitis pigmentosa and liver and kidney diseases. Kinesins are also becoming an important target for anti-cancer drugs.There are more than 100 different proteins that belong to the kinesin superfamily (41 in humans).The defining characteristic of the superfamily is the presence of a catalytic or motor domain (~340 amino acids) where the chemical energy from ATP hydrolysis is coupled to mechanical work production. The motor domain is highly conserved among all kinesins, yet there are kinesins with very different functionalities.There are kinesins that walk in opposite directions along the microtubule and there are others that depolymerize microtubules.
It is still not fully clear what conformational changes do kinesins go through during movement or how a very similar motor domains can perform seemingly very different functions, such as walking or depolymerizing microtubules.We investigate these issues using several experimental approaches such as site-directed mutagenesis, cryo-electron microscopy, and single molecule fluorescence microscopy. Cryo-electron microscopy is an ideal technique to obtain medium to high-resolution information of big macromolecular complexes such as the one formed by the motors proteins and their tracks. To trap different structural intermediates we use non-hydrolysable ATP analogues and rapid mixing techniques. To detect conformational changes in aqueous solutions as the proteins work, we developed a fluorescence polarization microscope that allows determining the orientation and mobility of a single fluorophore.
Asenjo, A. B., C. Chatterjee, D. Tan, V. DePaoli, William J. Rice, R. Diaz-Avalos, M. Silvestry, and H. Sosa, Structural model for tubulin recognition and deformation by kinesin-13 microtubule depolymerases. Cell Reports, 2013. 3(3): p. 759-768. http://www.cell.com/cell-reports/abstract/S2211-1247(13)00054-5
Zhang, D., A.B. Asenjo, M. Greenbaum, L. Xie, D.J. Sharp, and H. Sosa, A second tubulin binding site on the kinesin-13 motor head domain is important during mitosis. PLoS ONE, 2013. 8(8): p. e73075. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0073075
Sosa, H., Asenjo, A.B., and Peterman, E.J. (2010). Structure and dynamics of the kinesin-microtubule interaction revealed by fluorescence polarization microscopy. Methods Cell Biol 95, 505-519.
Asenjo A. B. and Sosa H. A Mobile Kinesin-Head Intermediate in the ATP-waiting State. (2009) Proc. Natl Acad. Sci. USA. 106: 5657-5662.
Tan D., Rice., and H. Sosa. (2008). Structure of the Kinesin13-Ring Complex. Structure 16: 1732-1739.
Tan. D. Asenjo, A.B., Mennella V., Sharp, D.J. and Sosa, H. (2006), Kinesin-13s Form Rings Around Microtubules. J. Cell Biol. 175: 25-31.
Asenjo, A, Weinberg, Y. and Sosa H. (2006). Nucleotide Binding and Hydrolysis Induces a Disorder-Order Transition in the Kinesin Neck-Linker Region. Nature Struct. & Mol. Biol. 13: 648-654.
Peterman, E. J. G., Sosa, H. and Moerner, W. E. (2004). Single-Molecule Fluorescence Spectroscopy and Microscopy of Biomolecular Motors. Ann. Rev. Phys. Chem. 55: 79-96.
Asenjo, A., Krohn, N. and Sosa H. (2003). Configuration of the two kinesin motor domains during ATP hydrolysis. Nature Struct. Biol. 10: 836-842.
Sosa, H., Peterman, E. J. G., Moerner, W. E., and Goldstein, L. S. B. (2001). ADP-Induced Rocking of the Kinesin Motor Domain Revealed by Single-Molecule Fluorescence Polarization Microscopy. Nature Struct. Biol. 8: 540-544
Peterman, E. J. G., Sosa, H., Goldstein, L. S. B., and Moerner, W. E. (2001). Polarized Fluorescence Microscopy of Individual and Many Kinesin Motors Bound to Microtubules. Biophys J.81: 2851-2863.
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