RESEARCH INTERESTS IN THE WALTER LAB
LAB INTERESTS
The above figure shows a cartoon diagram
of the generic cytokine signal transduction pathway that occurs for a number of
alpha-helical cytokines. In this system, cellular communication is
initiated by cytokine induced receptor oligomerization.
These oligomerization events activate intra-cellular
JAK kinases which subsequently phosphorylate
the intracellular domains of the receptors. These phosphorylated
sites recruit STAT (Signal Transducers Activators of Transcription)
molecules to the receptor complex. The STATs dimerize upon JAK kinase phosphorylation and translocate to the nucleus where they enhance gene
transcription events and ultimately cellular function.
The main objective of the lab is to define the structural and energetic basis for the specific recognition of cytokines by their receptors using x-ray crystallography and other biophysical methods including surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC). These studies provide basic knowledge on protein:protein interactions that are essential to the proper regulatory control of cellular functions. The molecules chosen for study are the alpha helical cytokines interferon gamma (IFN-g), interleukin 10 (IL-10), IFN-alpha and their receptors. The presence or absence of IFN-g and IL-10 have been implicated in numerous chronic inflammatory diseases including inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. The biological activities of IL-10 have also been linked to several B-cell malignancies. IFN-alpha is currently an important clinical drug in hairy cell leukemia and hepatitis C therapies.
The structural and energetic data obtained from these studies is clearly relevant for developing novel proteins and small molecules (agonists and antagonists) that can modulate the biological responses mediated by the receptor-ligand complexes. Our data is also being used for studies on protein folding and design.
LAB RESOURCES
The lab is well equipped for protein expression (E. coli,
Sf9, Drosophila, and Mammalian cell culture), protein purification (Pharmacia AKta and Perseptive Biocad systems), protein interaction analysis (Biacore 2000 surface plasmon
resonance machine) and protein crystallization. In addition to our own
computing network of clustered SGI workstations, the lab has full access to all
equipment available in the Center for
Biophysical Sciences and Engineering that is shared among six research
groups. Equipment available includes, 2 RAXIS IV's,
1 RAXIS II X-ray systems which are each equipped with liquid nitrogen cooling
systems. The lab also has dedicated access to the SERCAT synchrotron beamline located at the Advanced Photon Source (APS) in
GRADUATE EDUCATION
The Department
of Microbiology along with the Cellular
and Molecular Biology Program at UAB offer a large number of opportunities
for graduate education. Please contact Debbie Sirles
via email sirles@uab.edu for more
information.
POST-DOCTORAL / STAFF POSITIONS
A research position (Post-doc or Staff Scientist) is
available to design novel proteins and small molecules (agonists and
antagonists) that modulate the biological responses of interleukin-10 and the interferons. These helical cytokines play a critical
role in the proper regulation of the immune system and are currently used in
the treatment of inflammatory bowel disease, hairy cell leukemia, and hepatitis
C. Design efforts are guided by X-ray crystal structures of cytokine and
cytokine-receptor complexes. The qualified applicant will be involved in
the structure-based protein design, crystal structure determination, as well as
characterization of the receptor complexes using several different biophysical
methods. The applicant will also interact with several collaborators
involved in biological analysis of the designed molecules. Our lab is
funded and well equipped for these studies. Interested applicants may submit a
CV to Dr. Mark Walter at the
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