AMP-Kinase is a master sensor for cellular energy status. It is activated by high AMP/ATP levels and initiates changes in cellular energy utilization to compensate for low energy status such as increasing fatty acid oxidation, glucose uptake, and insulin sensitivity. Its activation is believed to be beneficial for patients with type II diabetes. The kinase exists as a heterotrimeric complex composed of an alpha-catalytic, gamma-AMP-binding, and beta-scaffolding subunits. The beta-subunit also contains a glycogen binding domain whose physiological relevance is not known. Preliminary data presented here indicates that the beta-subunit does not perform a scaffolding role in mammalian AMPK necessitating the re-evaluation of its model of assembly. A new model of assembly where beta binds to alpha which then binds gamma will be examined by FPLC analysis and co-immunoprecipitation studies using cellular lysates that express various mutants of each subunit. In addition, beta-subunit function will be further tested in vivo by creating betal- subunit mutant mice to address heterotrimer formation through deletion of its C-terminus, and by knock-in of a glycogen binding point mutation to determine the physiological significance of glycogen binding. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32DK069021-01A1
Application #
7057577
Study Section
Special Emphasis Panel (ZRG1-F06 (20))
Program Officer
Hyde, James F
Project Start
2005-12-01
Project End
2008-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
1
Fiscal Year
2005
Total Cost
$49,928
Indirect Cost
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142