Ph.D., Univ. of Chile, Santiago, 1987
Post-doctorate, Univ. of Pennsylvania, 1987-89
Post-doctorate, Mayo Clinic, Rochester, 1989-94
Assistant Professor at the University of Chile, 1995-97
Associate Professor, Centro de Estudios Cientificos de Santiago, 1995-97
About the Lab
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. These techniques overcome the restrictions of traditional bulk biochemical studies by focusing on individuals of molecules.
Our research focuses on the dynamics and mechanics of proteins using single-molecule manipulation techniques. Research Highlights: i) Mutations in Polycystin-1 cause polycystic kidney disease which is a common life-threatening genetic disease. We have discovered that Polycystin-1 has unique mechanical properties (Qian et al., J Biol Chem 2005; Xu et al., J. Biophysics 2013) and that pathogenic mutations can alter its nano-mechanics (Ma et al, J Biol Chem 2009, 2010); ii) We have found that titins are finely tuned to their micro-environment and that titin domains can fold under an applied force which hints for a previously uncharacterized folding-based spring mechanism (Bullard et al., PNAS 2006). We discovered that titin protein kinase domains from have mechanical properties that are consistent with a function as effective force sensor (Greene et al, Biophys J. 2008); iii) Elastin and collagens are key structural component of the extracellular matrix. Despite its fundamental importance in tissue elasticity very little is known about the mechanical properties of native elastin and collagen fibers at the nano-molecular level. We have found that single tropoelastin molecules (a soluble precursor of elastin) can be stretched/relaxed hundreds of times, with no signs of hysteresis or molecular fatigue (Baldock et al., PNAS 2011). These mechanical properties make elastin an ideal molecular spring which is perfectly designed to undergo many stretch/relaxation cycles during the normal operation of different tissues (Holst et al., Nature Biotechnol. 2010); iv) Little is known about the molecular mechanisms that mediate myosin biogenesis into semi-crystalline arrays in muscle cells. We know that the molecular chaperones UNC-45 and Hsp90 are involved, but the actual mechanism has remained enigmatic. Using in vitro assays, we have now found surprising results regarding the interactions between UNC-45 and Hsp90 with myosin (Kaiser et al., Biophys J. 2012; Bujalowski et al., Biophys J. 2014; Nicholls et al., FEBS let 2015). A keystone of our findings is a novel chaperone bound state of myosin that, to our knowledge, reconciles all previous genetic, biochemical and structural data pertaining to this system.
Nanomechanics of Ig-like domains
Oberhauser, A.F., Marszalek, P.E., Erickson, H.P., and Fernandez, J.M. The molecular elasticity of tenascin, an extracellular matrix protein. (1998) Nature, 393:181-185.
Oberhauser, A.F., Hansma, P.K., Carrion-Vazquez, M., and Fernandez, J.M. Stepwise unfolding of titin under force-clamp AFM. (2001) Proc. Natl. Acad. Sci., 98:468-472.
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. (2006) Proc. Natl. Acad. Sci. 103(12) 4451–4456.
Garcia, T., Oberhauser AF and Braun W. Mechanical Stability and Differentially Conserved Physical-chemical Properties of Titin Ig-domains. (2008) Proteins Sep 25;75(3):706-718.
Greene, D.N., Garcia T., Sutton, RB, Gernert K. M., Benian, G. M., & Oberhauser AF. Single-molecule force spectroscopy reveals a stepwise unfolding of C. elegans giant protein kinase domains. (2008) Biophys J. 95(3):1360-70. [Figure featured on journal cover]
Fuson, K., Ma, L., Sutton, RB & Oberhauser AF. The C2 domains of human Synaptotagmin 1 have distinct mechanical properties (2009). Biophys J. 96(3):1083-90.
Baldock C, Oberhauser AF, Ma L, Lammie D, Siegler V, Mithieux SM, Tu Y, Chow JY, Suleman F, Malfois M, Rogers S, Guo L, Irving TC, Wess TJ, Weiss AS. Shape of tropoelastin, the highly extensible protein that controls human tissue elasticity. (2011) Proc Natl Acad Sci U S A.108(11):4322-7.
Holst. J, Weiss, A., A.S., Watson, S., Nivison–Smith, L., Eamegdool, S., Ma, L., Oberhauser, A.F. and Rasko, J. “Substrate elasticity provides mechanical signals for the expansion of hemopoietic stem and progenitor cells” (2010) Nature Biotechnology. Oct; 28(10):1123-8.
Nanomechanics of Polycystic Kidney Disease Proteins
Qian, F., Wei, W., Germino, G.G., and Oberhauser, A.F. The Nanomechanics of Polycystin-1 extracellular region. (2005) J Biol Chem. 280(49):40723-30.
Ma L, Xu M., & Oberhauser A.F. Naturally occurring osmolytes modulate the nano-mechanical properties of Polycystic Kidney Disease (PKD) domains. (2010) J Biol Chem. 285(49):38438-43.
Ma L, Xu M, Forman JR, Clarke J. & Oberhauser A.F. Naturally occurring mutations alter the stability of polycystin-1 PKD domains. (2009). J Biol Chem. 284(47):32942-9.
Ma L, Xu M., & Oberhauser A.F. Single-Molecule Force Spectroscopy of Polycystic Kidney Disease Proteins. (2012). Methods Mol Biol. 875:297-310.
Xu M., Ma L, Bujalowski, P., Qian, F. Sutton, B. & Oberhauser A.F. Analysis of the REJ Module of Polycystin-1 Using Molecular Modeling and Force-Spectroscopy Techniques. (2013). Journal of Biophysics vol 2013; [selected as a must read paper by “Faculty of 1000 Biology].
Kaiser, CM, Bujalowski, P., Ma, L., Anderson, J., Epstein H.F., and Oberhauser A.F. Tracking UNC-45 Chaperone-Myosin Interaction with a Titin Mechanical Reporter. (2012) Biophysical Journal 102 (9): 2212-2219.
Bujalowski, P., Nicholls, P., Oberhauser AF. Myosin Specific UNC-45b Chaperone: role of its Domains in the Interaction with the Myosin Motor Domain. (2014) Biophysical Journal Aug5;107(3):654-61. [Featured in the New and Notable section]
Nicholls, P., Bujalowski, P.J, Epstein, HF, Boehning, DF, Barral, JM, Oberhauser AF. Chaperone-mediated reversible inhibition of the sarcomeric myosin power stroke. (2014) FEBS letters Nov 3;588(21):3977-81.
Bujalowski, P.J, Nicholls, P., Barral, JM, Oberhauser AF. Thermally-induced structural changes in an armadillo repeat protein suggest a novel thermosensor mechanism in a molecular chaperone. (2015) FEBS letters Jan 2;589(1):123-30.
Oberhauser, AF & Carrion-Vazquez, M. Mechanical biochemistry of proteins one molecule at a time (2008). J Biol Chem; 283(11):6617-21.
Galera-Prat A, Gómez-Sicilia A, Oberhauser AF, Cieplak M, Carrión-Vázquez M. Understanding biology by stretching proteins: recent progress. (2010)Curr Opin Struct Biol.;20(1):63-69.
Bujalowski, P., Oberhauser AF. Tracking Unfolding and Refolding Reactions of Single Proteins using Atomic Force Microscopy Methods. (2013) METHODS Apr 1;60(2):151-60.