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 (IAsys
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, 2 HiStars, and 1 DIP X-ray detector which are each
equipped with liquid nitrogen cooling systems. The Center also contains a
large computing center with SGI workstations as well as multiprocessor Onyx and
Origin SGI machines for CPU and graphically intensive studies.
Biophysical analysis equipment include Mass Spectrometers, a Pharmacia Biacore
machine, and serveral micro calorimeters. Several additional campus
centers are well equipment for ultracentrifugation, Mass Spec (MALDI-TOF,
Electro Spray), DNA sequencing and Flow Cytometry.
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 University of Alabama at Birmingham (UAB). UAB is
an equal opportunity employer. Salary for the position is dependent on
the applicant's experience. If interested contact Mark Walter at walter@uab.edu .
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