Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 293, Issue 44, Pages 16994-17007Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.004101
Keywords
AMP-activated kinase (AMPK); biophysics; diabetes; metabolic regulation; cancer; ADaM site; DEER
Categories
Funding
- Jules Stein Professorship endowment
- Van Andel Research Institute
- National Institutes of Health [R01 GM102545, R01 GM129436, R01 EY05216, T33 EY07026, 5P41EB001980, R01 DK071662]
- National Natural Science Foundation of China [31300245]
- Ministry of Science and Technology (China) [2012ZX09301001, 2012CB910403, 2013CB910600, XDB08020303, 2013ZX09507001]
- Amway (China)
Ask authors/readers for more resources
AMP-activated protein kinase (AMPK) is a master regulator of energy homeostasis and a promising drug target for managing metabolic diseases such as type 2 diabetes. Many pharmacological AMPK activators, and possibly unidentified physiological metabolites, bind to the allosteric drug and metabolite (ADaM) site at the interface between the kinase domain (KD) in the -subunit and the carbohydrate-binding module (CBM) in the -subunit. Here, using double electron-electron resonance (DEER) spectroscopy, we demonstrate that the CBM-KD interaction is partially dissociated and the interface highly disordered in the absence of pharmacological ADaM site activators as inferred from a low depth of modulation and broad DEER distance distributions. ADaM site ligands such as 991, and to a lesser degree phosphorylation, stabilize the KD-CBM association and strikingly reduce conformational heterogeneity in the ADaM site. Our findings that the ADaM site, formed by the KD-CBM interaction, can be modulated by diverse ligands and by phosphorylation suggest that it may function as a hub for integrating regulatory signals.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available