NSF Org:	MCB Division of Molecular and Cellular Biosciences
Recipient:
Initial Amendment Date:	March 10, 1992
Latest Amendment Date:	November 21, 1994
Award Number:	9117799
Award Instrument:	Continuing Grant
Program Manager:	Marcia Steinberg MCB  Division of Molecular and Cellular Biosciences BIO  Directorate for Biological Sciences
Start Date:	February 15, 1992
End Date:	January 31, 1996 (Estimated)
Total Intended Award Amount:	$270,000.00
Total Awarded Amount to Date:	$270,000.00
Funds Obligated to Date:	FY 1992 = $90,000.00 FY 1993 = $90,000.00 FY 1994 = $90,000.00
History of Investigator:	Ross Dalbey (Principal Investigator) dalbey@chemistry.ohio-state.edu Marita King (Former Principal Investigator)
Recipient Sponsored Research Office:	Ohio State University Research Foundation -DO NOT USE 1960 KENNY RD Columbus OH  US  43210-1016 (614)688-8734
Sponsor Congressional District:	03
Primary Place of Performance:	Ohio State University 1960 KENNY RD COLUMBUS OH  US  43210-1016
Primary Place of Performance Congressional District:	03
Unique Entity Identifier (UEI):	QR7NH79713E5
Parent UEI:
NSF Program(s):	MOLECULAR BIOCHEMISTRY
Primary Program Source:	app-0193  app-0194
Program Reference Code(s):	0000, OTHR
Program Element Code(s):	116600
Award Agency Code:	4900
Fund Agency Code:	4900
Assistance Listing Number(s):	47.074

ABSTRACT

With the goal of elucidating molecular mechanisms by which calmodulin-activated enzymes aid transformation of CA2+-signals into biochemical responses, this project addresses relationships between structure, function, and regulation of the type II calmodulin-dependent protein kinase. The major target is a recombinant, monomeric form of the kinase which contains catalytic and regulatory domains but lacks the association domain. Site-specific mutagenesis will be used to produce additional forms of the kinase and calmodulin. How Mg2+, calmodulin, substrates, and autophosphorylation regulate domain folding, interactions, and topographical arrangements will be a major focus. Chemical crosslinking and active site-directed reagents will be used to probe sequences of events in kinase activation. Fluorescent probes will be attached to specific sites of calmodulin and the kinase for fluorescence and energy transfer studies; suitable metal ions and nucleotide analogs provide additional fluoroprobes. Changes in circular dichroism and in the susceptibility of the protein to proteolytic cleavage will be correlated with corresponding changes in kinase activity and calmodulin- dependence. The X-ray structure of the truncated kinase will be determined in a collaborative project. Current working models of the structure and regulation of this prominent calmodulin-dependent enzyme will be refined by computer modeling.

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