Interferons (IFNs) are known for their anti-viral, anti-tumor, anti- proliferative, and immune regulatory activities. The current understanding of the pathway of type I IFN signaling seems fairly complete at a global level. Upon receiving the extracellular IFN signal, the receptors IFNAR-l and IFNAR-2c dimerize bringing their respectively bound kinases Tyk2 and Jak1 as well as the IFNAR-2c bound STAT2 and STAT1 in close proximity at the cytoplasmic end of the receptor. This facilitates a series of critical phosphorylations of first the IFNAR-1 receptor followed by STAT2 and then STAT1 phosphorylation resulting in the release of the activated STAT1/STAT2 heterodimer. Although this pathway has been mapped out at a global level, the crucial atomic details of all the proteins involved and their molecular interactions at every stage in this pathway are not known. Therefore, this proposal focuses on determining the structures of complexes between STAT2, the cytoplasmic domain of IFNAR-2c, STAT1, and the phosphorylated cytoplasmic domain of IFNAR-1 at various stages in the STAT1/STAT2 activation pathway by protein crystallography. These crystal structures will allow a detailed understanding of the STAT activation part of the type I IFN signaling pathway.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM019665-02
Application #
6018422
Study Section
Special Emphasis Panel (ZRG3-PB (01))
Project Start
1999-09-04
Project End
Budget Start
1999-09-04
Budget End
2000-09-03
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
017730458
City
Cleveland
State
OH
Country
United States
Zip Code
44195