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.
Kinesin-13s form rings around microtubules
Kinesin-13s form rings around microtubules. Tan D., Asenjo A., Mennella V., Sharp D, Sosa, H. J.Cell Biol. (October 9).(2006)
Nucleotide binding induces a disorder to order transition in the kinesin neck-linker region. Asenjo, A., Weinberg Y, and Sosa H. Nature Struct. & Mol. Biol. 13: 648-654.(2006).
Single-Molecule Fluorescence Spectroscopy and Microscopy of Biomolecular Motors. Peterman, E. J. G., Sosa, H. and Moerner, W. E. Ann. Rev. Phys. Chem. 55: 79-96. (2004)
Configuration of the two kinesin motor domains during ATP hydrolysis. Asenjo, A., Krohn, N. and Sosa H.Nature Struct. Biol. 10: 836-842. (2003).
ADP-Induced Rocking of the Kinesin Motor Domain Revealed by Single-Molecule Fluorescence Polarization Microscopy. Sosa, H., Peterman, E. J. G., Moerner, W. E., and Goldstein, L. S. B. Nature Struct. Biol. 8, 540-544. (2001).
Polarized Fluorescence Microscopy of Individual and Many Kinesin Motors Bound to Microtubules. Peterman, E. J. G., Sosa, H., Moerner, W. E., and Goldstein, L. S. B. Biophysical J. 81: 2851-2863 (2001).
A model for the microtubule-Ncd motor protein complex obtained by cryo-electron microscopy and image analysis. Sosa, H., Dias, D. P., Hoenger, A., Whittaker, M., WilsonKubalek, E., Sablin, E., Fletterick, R. J., Vale, R. D., and Milligan, R. A. Cell 90, 217-224. (1997).
Three-Dimensional Structure of Ncd-Decorated Microtubules Obtained By a Back-Projection Method. Sosa, H., and Milligan, R. A.. J Mol Biol 260, 743-755. (1996).
Material in this section is provided by individual faculty members who are solely responsible for its accuracy and content.
Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
Ullmann Building, Room 217
Bronx, NY 10461