Education and Training
PhD in Physiology & Biophysics, University of Chile, Santiago, Chile
Post-Doctoral in Physiology & Biophysics, University of Pennsylvania, Pennsylvania
Post-Doctoral in Physiology & Biophysics, Mayo Clinic, Rochester, Minneapolis
Single-molecule methods have emerged as powerful tools in life science research. These techniques allow the detection and manipulation of individual biological molecules and investigate, with unprecedented resolution, their conformations and dynamics at the nanoscale level. In my research I apply single-molecule techniques to biological problems that are important for human diseases
Single-molecule methods have emerged as powerful tools in life science research. These techniques allow the detection and manipulation of individual biological molecules and investigate, with unprecedented resolution, their conformations and dynamics at the nanoscale level. In my research I apply single-molecule techniques to biological problems that are important for human diseases.
The goal of my current research is to elucidate the precise molecular mechanisms by which the chaperones UNC-45 and Hsp90 assist in the folding of the myosin head which is critical for sarcomere assembly during development and repair of stress-induced damage to sarcomeres in mature muscle. Developing an understanding of these mechanisms is a problem at the core of muscle development and function.
Guided by our recent discoveries, we hypothesize that during myosin assembly or repair, UNC-45 assists the myosin head to attain its native conformation and subsequently locks it in a state that prevents premature powerstrokes; this state is relieved by the ubiquitous chaperone Hsp90 upon successful assembly into the sarcomere or repair of myosin heads. My group recently devised novel approaches to analyze myosin:chaperone interactions using a combination of single-molecule atomic force microscopy, site specific fluorescence probes and in vitro myosin motility techniques, that enable us to study, for the first time, the effects of these chaperone proteins on the myosin motor domain folding and function in mechanistic detail.
Our hypothesis, if confirmed, will represent a new paradigm in the biology of myosins, with potential novel therapeutic approaches not only for striated muscle disorders stemming from mutations in sarcomeric proteins (skeletal myopathies and cardiomyopathies), but also for the problem of tumor invasiveness.
Oberhauser, A., Monck, J.R., Balch, W.E. and Fernandez, J.M. Exocytotic fusion is activated by Rab3 peptides. Nature 360:270-273, 1992.
Oberhauser, A.F. and Fernandez, JM. A fusion pore phenotype in mast cells of the ruby-eye mouse. Proc. Natl. Acad. Sci. 93:14349-14354, 1996.
Oberhauser, A.F., Marszalek, P.E., Erickson, H.P., and Fernandez, J.M. The molecular elasticity of tenascin, an extracellular matrix protein. Nature 393:181-185, 1998.
Oberhauser, A.F., Marszalek, P.E., Carrion-Vazquez, M., and Fernandez, J.M. Single protein misfolding events captured by atomic force microscopy. Nature Struct. Biol. 6:1025-1028, 1999.
Qian, F., Wei, W., Germino, G.G., and Oberhauser, A.F. The Nanomechanics of Polycystin-1 extracellular region. J. Biol. Chem. 280(49):40723-30, 2005.
Bullard, B., Garcia, T., Benes., V., Leake, M., Linke, W., and Oberhauser, A.F. The Molecular Elasticity of the Insect Flight Muscle Proteins Projectin and Kettin. Proc. Natl. Acad. Sci. 103(12) 4451-4456, 2006.
Kaiser, C.M., Bujalowski, P.J., Ma, L., Anderson, J., Epstein, H.F. and Oberhauser, A.F. Tracking UNC-45 chaperone-myosin interaction with a titin mechanical reporter. Biophys J. 102(9):2212-9, 2012.
Bujalowski, .PJ., Nicholls, P. and Oberhauser, A.F. UNC-45B chaperone: the role of its domains in the interaction with the myosin motor domain. Biophys J. 107(3):654-61, 2014.
Nicholls, P., Bujalowski, P.J., Epstein, H.F., Boehning, D.F., Barral, J.M. and Oberhauser, A.F. Chaperone-mediated reversible inhibition of the sarcomeric myosin power stroke. FEBS Lett. 588(21):3977-81, 2014.
Bujalowski, P.J., Nicholls, P., Barral, J.M. and Oberhauser, A.F. Thermally-induced structural changes in an armadillo repeat protein suggest a novel thermosensor mechanism in a molecular chaperone. FEBS Lett. 589(1):123-30, 2015.