15/09/2020 - Press release
The research group of GPCR Drug Discovery at the Hospital del Mar Medical Research Institute (IMIM), in collaboration with the Indian Institute of Technology in Kanpur, has deciphered how nature adjusts the response of the human cell to abundant extracellular stimuli (e.g., smell, taste, light, hormones, etc.).
When a cell receives an extracellular stimulus, it initiates a signaling process that can result in major physiological changes. This process is mediated by cell membrane proteins such as G protein coupled receptors (GPCRs). Depending on the stimulus, those receptors regulate cell activity through different molecular mechanisms.
The researchers have been able to interpret one of the main molecular mechanisms of cell regulation. "Using biophysical and biochemical assays combined with state-of-the-art computer simulations, we have been able to decipher a phosphorylation code that fine-tunes the cell behaviour" explains Dr. Jana Selent, head of the IMIM GPCR Drug Discovery group and one of the co-coordinators of this study.
Extracellular stimulation of GPCRs leads to its activation and subsequently to the phosphorylation of its long intracellular tail. Interestingly, there are multiple phosphorylation patterns of the receptor tail - each of them linked to a specific signaling response. The phosphorylation code is read by intracellular proteins known as β-arrestins. In response, they typically silence the receptor and modulate intracellular kinases, which have a global impact on cell behaviour related to gene expression, cell survival and cell death. "Until now, the phosphorylation code and the involvement of arrestins in deciphering it has been an open question" explains Dr. Selent. "We have discovered the underlying molecular mechanism of how arrestin reads and translates a specific phosphorylation pattern into a cellular response" she adds.
To carry out this research, Dr. Arun Shukla, of the Indian Institute of Technology in Kanpur, who is a leading scientist and co-coordinator of the study, conducted a multitude of biophysical and biochemical assays which impressively proved that specific phosphorylation codes regulate differently cell function.
To understand this process at a molecular level, Dr. Selent's group generated large-scale computer simulations that gave rise to surprising high-resolution structural insights. They discovered that a specific phosphorylation code induces a distinct rotation in the three-dimensional structure of arrestin that is translated into a particular cellular outcome.
GPCR-induced signaling into the cell is involved in almost any physiological process throughout the human body. This is reflected by the fact that more than 30% of currently used drugs act on this type of receptor. "Therefore, our molecular findings create new opportunities to rethink current treatment approaches and, in addition, to design novel therapeutic strategies for important diseases such as cancer or Alzheimer's" explains Dr. Tomasz Stepniewski - who is a co-author of this study and part of the GPCR Drug Discovery group.
"Now that we have discovered the first piece of the puzzle, that is, how arrestins are able to read different functional information that is encoded in a specific phosphorylation pattern, we can begin to design drug candidates that are capable of (over)writing phosphorylation codes to improve or prevent specific diseases conditions" concludes Dr. Selent.
Video: “The secret code that regulates the celular behaviour”. Font IMIM
Photo: Jana Selent PhD and Tomasz Stepniewski PhD. Font: IMIM
Reference:"Distinct phosphorylation sites in a prototypical GPCR differently orchestrate β-arrestin interaction, trafficking, and signaling" BY HEMLATA DWIVEDI-AGNIHOTRI, MADHU CHATURVEDI, MITHU BAIDYA, TOMASZ MACIEJ STEPNIEWSKI, SHUBHI PANDEY, JAGANNATH MAHARANA, ASHISH SRIVASTAVA, NATARIN CAENGPRASATH, AYLIN C. HANYALOGLU, JANA SELENT, ARUN K. SHUKLA. SCIENCE ADVANCES11 SEP 2020 : EABB8368. https://advances.sciencemag.org/content/6/37/eabb8368
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