A large number of key biological signaling processes are mediated and regulated via GTP binding proteins. Members of this superfamily of proteins serve as biological switches, turning biological signaling processes on or off in response to incoming extracellular signals. Their unique switching capability arises from a conformational reorganization in the molecule which depends on the nature of the bound ligand. In response to a signaling event which arises from a process initiated by; for example, growth factor binding, G proteins bind GTP, become activated, and interact with downstream effector proteins. Sometime later, the internal GTPase activity hydrolyzes GTP to GDP, terminating the signal. This process is modulated by a number of regulatory proteins which can increase the GTPase activity or can increase or decrease the affinity for nucleotide. For many cases of unregulated growth, the transformed phenotype is linked to a mutated GTP binding protein, making this class of protein of great biomedical interest. The rho GTP binding proteins are a subfamily of the ras superfamily of GTP binding proteins. The rho proteins are involved in the assembly of macromolecular complexes linked to cytoskeletal reorganization and are implicated in the signal transduction pathway of several oncoproteins, in particular Dbl. The Oswald group, in collaboration with Wagner at Harvard, Sutcliffe of Leicester and Cerione of Cornell, has solved the solution structure of the complex of Cdc42s with GDP using NMR spectroscopy. The current proposal focuses on extending this structural information, by seeking to determine the three dimensional structure of Cdc42s by itself and complex with an effector domain and in complex with a GTP analog. Studies of the interaction with the catalytic domain of an activating protein with Cdc42s, and the characterization of the structure of a chimera constructed to examine the role of the """"""""rho domain"""""""" in the structure of Cdc42s, are also proposed.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM056233-03
Application #
6181291
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Program Officer
Chin, Jean
Project Start
1998-05-01
Project End
2002-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
3
Fiscal Year
2000
Total Cost
$184,135
Indirect Cost
Name
Cornell University
Department
Other Basic Sciences
Type
Schools of Veterinary Medicine
DUNS #
City
Ithaca
State
NY
Country
United States
Zip Code
14850