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New Coding Methods and 19F-NMR Techniques Disclose Phospho-coding Mechanisms of G Protein Coupled Receptor

Sep 14, 2015     Email"> PrintText Size

G Protein Coupled Receptor (GPCR), which contributes to the development of modern pharmacology, is one of the most important drug targets. Ten Nobel Prizes have been awarded to the research related to the field of GPCR, including the latest one in 2012. There are two general signaling pathways mediating the majority of GPCR functions in the research, G protein and Arrestin. However, the detailed mechanisms of how G protein or Arrestin recognizes specific GPCR information and translates it into signaling output remain unclear.

In a study published in Nature Communications, Prof. WANG Jiangyun’s group from Institute of Biophysics of Chinese Academy of Sciences together with Prof. SUN Jinpeng from Shandong University discovered that Arrestin dictates signaling-mediated mechanisms by recognizing GPCR specific phosphor-coding information and putting forward important new hypothesis.

For decades, receptor C-terminal phosphorylation barcodes (phosphorylation by different kinases) have been hypothesized to dictate distinct receptor signaling through arrestins. This hypothesis may explain the diverse functions of various GPCRs in different cellular contexts. However, the exact phospho-barcode message and the accompanying mechanism for this signaling control have not been defined.

There is no defined phosphorylation sequence information that correlates with their distinct Arrestin-mediated functions and the conformational heterogeneity of Arrestin poses significant challenges for these studies. Researchers even doubt about the existence of the true "phospho-barcode” of the receptor, calling it a “floating hypothesis”. The mechanisms of receptor phosphorylation barcode and a structural understanding of the phosphorylation coded specific Arrestin conformations are in great need to clarify these uncertainties.

Prof. WANG Jiangyun and Prof. SUN Jinpeng used novel unnatural amino acid incorporation technology and 19F-NMR spectroscopy in this study. The application of site-directed 19F-NMR deciphered the specific receptor-phospho-code read by Arrestins. For example, whereas a phospho-binding sequence of 1-4-6-7 pattern determines the specific β-arrestin-1 conformation for clathrin recruitment, a different receptor ‘tune,’ 1-5, provides the SRC signaling order. Moreover, 19F-NMR and cellular studies demonstrated that distinct Arrestin conformational states induced by specific phosphorylation patterns are coupled to their selective functions, which are applied to many GPCR members.

This study brought up a “flute model” for GPCR-Arrestin working mechanism: the receptor phospho-C-tail works like the fingers of a magic hand, manipulating music from the receptor by touching on the N-terminal hole of the Arrestin (like a flute) and the combination of the fingers generates different signaling tunes.

In general, the combination of all phosphate binding sites in single Arrestin member accommodates more than 1,000 patterns (210 – 1= 1023) that can produce a plethora of Arrestin conformations for numerous downstream protein interactions. Therefore, phospho-binding concave renders enough space for its recognition of plethora phosphorylation states of numerous GPCRs, which generates specific Arrestin conformations for selective functions to shape one side for functional diversity of many GPCRs (more than 800 in human genome).


Figure: Arrestin mediated signaling directed by phospho-coding of the receptor (Image by WANG Jiangyun’s group) 


(Editor: 陈潇)


WANG Jiangyun

Institute of Biophysics

E-mail: jwang@ibp.ac.cn

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