Transmembrane signaling plays a central role in all of biology, allowing cells to sense and respond to their environment. In humans, integral membrane receptors mediate the effects of hormones, neurotransmitters, cytokines, and a multitude of other signaling molecules. The PAQR receptors are a poorly characterized family of transmembrane receptors, found in organisms ranging from bacteria to humans. Recently, two PAQR receptors have attracted particular attention because they mediate the effects of a protein hormone called adiponectin. Adiponectin has been shown to induce profound insulin-sensitizing and cardioprotective effects in mouse models of diabetes and cardiovascular disease, but little is known regarding the molecular mechanisms of adiponectin signaling. To unravel the molecular details of adiponectin receptor signaling, we will pursue a combination of structural and biochemical studies of adiponectin and its receptors, with the long term goal of developing a detailed molecular understanding of signaling through the adiponectin receptors and broader PAQR family.

Public Health Relevance

The protein hormone adiponectin has been shown to exert strong beneficial effects in animal models of diabetes and cardiovascular disease. The proposed work seeks to unravel the molecular details underlying adiponectin function, with the long-term goal of facilitating the development of therapeutic approaches targeting this important pathway.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Early Independence Award (DP5)
Project #
5DP5OD021345-03
Application #
9349368
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Basavappa, Ravi
Project Start
2015-09-15
Project End
2020-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Type
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Paek, Jaeho; Kalocsay, Marian; Staus, Dean P et al. (2017) Multidimensional Tracking of GPCR Signaling via Peroxidase-Catalyzed Proximity Labeling. Cell 169:338-349.e11
Pascolutti, Roberta; Sun, Xianqiang; Kao, Joseph et al. (2016) Structure and Dynamics of PD-L1 and an Ultra-High-Affinity PD-1 Receptor Mutant. Structure 24:1719-1728
Zimmerman, Brandon; Kelly, Brendan; McMillan, Brian J et al. (2016) Crystal Structure of a Full-Length Human Tetraspanin Reveals a Cholesterol-Binding Pocket. Cell 167:1041-1051.e11