Jill Trewhella
Professor of Chemistry
B.S. University of New South Wales
Ph.D. University of Sydney
Research
My research laboratory is focused on how bio-molecules communicate in order to carry out functions that require multiple molecular actors working in concert; for example in muscle or in the glycogen degradation cascade that is initiated as part of the "fright and flight" response. In this work, we are very interested in understanding how proteins use "conformational language" to communicate within complex molecular networks or assemblies inside cells in order to achieve a coordinated response to an external stimulus. This coordination is often accomplished with the help of nature's "second messengers" inside cells that are released when a signal molecule (the first messenger) binds at the surface of a cell. The simplest intra-cellular second messenger is divalent calcium (Ca 2+). Another class is the cyclic nucleotides (cAMP and CGMP) are another.
We use small-angle x-ray and neutron scattering to complement high resolution crystallographic and NMR structural tools, enabling us to probe the solution conformations of proteins and the complexes they form in a wide variety of conditions. We are currently using scattering, in combination with other structural approaches including computational modeling, to study Ca 2+ signaling in cardiac troponin, the protein complex that sits on the thin filaments of muscle and regulates the contraction/relaxation cycle. We are very interested in understanding the differences in how the Ca 2+ signal is modulated in cardiac versus skeletal muscle by changes in charge (either by phosphorylation or mutation of specific sites) in order to understand the molecular basis of specific heart diseases. Another project focuses on how cyclic nucleotides regulate kinase activation in a variety of signaling networks. For example, we are using scattering techniques and structural modeling to understand the similarities and differences between the cAMP- and cGMP- dependent protein kinases, and how different isoforms accomplish their distinctive functions.
My laboratory is split between two continents, and we enjoy doing science in two distinct cultural and geographic settings. Unique neutron scattering facilities in Australia are a major attraction down under, enhancing the science we can accomplish.
Different Isoforms of the cAMP-binding Protein Kinase interacting with membrane bound receptors.
References
1. Vigil D, Blumenthal DK, Brown S, Taylor SS, Trewhella J (2004) Differential Effect of Substrate on Type I and Type II PKA Holoenzyme Dissociation. Biochemistry 43:5629
2. Heller WT, Vigil D, Brown S, Blumenthal DK, Taylor SS, Trewhella J (2004) C Subunits Binding to the Protein Kinase A RI a Dimer Induce a Large Conformational Change. J. Biol. Chem. 279:19084
3. Vigil D, Blumenthal DK, Heller WT, Brown S, Canaves JM, Taylor SS, Trewhella J (2004) Conformational Differences Among Solution Structures of the Type I a , II a and II b Protein Kinase A Regulatory Subunit Homodimers: Role of the Linker Regions. J. Mol. Biol. 337:1183
4. Heller WT, Finley N, Dong W-J, Timmins P, Cheung HC, Rosevear PR, Trewhella J (2003) Small-Angle Neutron Scattering with Contrast Variation Reveals Spatial Relationships Between the Three Subunits in the Ternary Cardiac Troponin Complex and the Effects of Troponin I Phosphorylation. Biochemistry 42:7790
5. Wall ME, Francis SH, Corbin JD, Grimes K, Richie-Jannetta R, Kotera J, Macdonald BA, Gibson RR, Trewhella J (2003) Mechanisms Associated with cGMP Binding and Activation of cGMP-Dependent Protein Kinase. Proc. Natl Acad. Sci. USA
