Andres F. Oberhauser, PhD
Professor, Department of Neuroscience & Cell Biology
Tel: (409) 772-1309
Fax: (409) 747-2187
E-mail: afoberha@utmb.edu
Campus Location:5.212A Research Bldg 17
Mail Route: 06203
Research
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 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 2014).
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. v) The muscle-specific
molecular chaperone UNC-45B is known to be involved in myosin folding
and is trafficked to the sarcomeres A-band during thermal stress.
We recently identified a temperature-dependent structural change in the
UCS chaperone domain of UNC-45B that occur within a physiologically
relevant heat-shock range. We show that distinct changes to the
armadillo repeat protein topology result in exposure of hydrophobic
patches, and increased flexibility of the molecule (Bujalowski et al;
FEBS lett 2015). We suggest that these changes may function to suppress
aggregation under stress by allowing binding to a wide variety of
aggregation prone loops on its myosin client.
Selected Publications
Publications