Research performed by Dr. Sangita Sinha, Assistant Professor of Chemistry and Biochemistry, has been published in the major international science journal, Cell.
The research team, which included scientists from six institutions in the United States, has identified a new protein, Beclin 2, that is involved in autophagy and required for the degradation of several G protein-coupled receptors (GPCRs). In mammals, decreased levels of Beclin 2 results in decreased embryonic viability, increased levels of brain GPCRs such as the cannabinoid receptors, elevated food intake, obesity and insulin resistance. This research is published in the August 2013 online issue of the journal Cell at http://www.cell.com/abstract/S0092-8674(13)00943-4.
Autophagy, an essential cellular pathway, is responsible for the recycling of nutrients and generation of energy inside the cell by facilitating the clearance and degradation of macromolecular assemblies that are either damaged, harmful or no longer needed by the cell. Autophagy occurs in all eukaryotic organisms, ranging from yeast to humans. Several proteins, called autophagy effectors, are required to carry out this essential cellular process. Beclin 2 is similar in amino acid sequence to another previously autophagy effector, Beclin 1, which is essential for the survival of all eukaryotic organisms. However, Beclin 2 is found only in higher vertebrates like mammals, where it carries out additional functions that are required for the maintenance of more complex cells.
GPCRs are the largest family of cell-surface receptors encoded in the human genome, and constitute a key mechanism for controlling cellular responses to environmental cues. Binding of different ligands to these receptors results in activation of various signaling pathways inside cells allowing the cell to respond to various environmental stimuli. Ligand-bound, activated receptors are internalized by the cell. Internalized GPCRs may be stripped of their ligands and returned to the surface, allowing the signaling process to be reactivated, or the GPCRs may be degraded resulting in a down-regulation of the signaling process.
The discovery of the role Beclin 2 plays in this process helps explain the mechanism by which GPCR signaling is down-regulated. Key work done by Dr. Sinha helped identify regions of Beclin 2 that were different from Beclin 1. This enabled the production of Beclin 2-specific antibodies that were critical for many of the experiments reported in the paper. This information was also used to identify Beclin 2 protein interactions that were different from Beclin 1. Ultimately, this led to the identification of the unique function of Beclin 2 in down-regulating GPCRs.
Dr. Sinha, along with graduate students Minfei Su and Yue Li in the Department of Chemistry and Biochemistry at NDSU, continue the research on Beclin 2. The ultimate goal of their ongoing research is to elucidate the three-dimensional atomic resolution structure of Beclin 2 in order to understand the mechanism by which it facilitates the degradation of GPCRs.