TY - JOUR
T1 - Mechanistic Understanding of the Phosphorylation-Induced Conformational Rigidity at the AMPA Receptor C-terminal Domain
AU - Chatterjee, Sudeshna
AU - Dutta, Chayan
AU - Carrejo, Nicole C.
AU - Landes, Christy F.
N1 - Funding Information:
This work is supported by the Welch Foundation (grant no. C-1787). C.D. thanks the National Science Foundation (grant no. CHE-1808382) for funding. The authors thank Prof. Vasanthi Jayaraman and her group at UTHSC for the collaboration on the NMDA receptor protein study shown in the Supporting Information . The authors thank all of the members of the Landes research group, Prof. Stephan Link and his research group for helpful discussions.
Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2019/9/3
Y1 - 2019/9/3
N2 - Phosphorylation at the intracellular C-terminal domain (CTD) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors induces conformational rigidity. Such intracellular alterations to the AMPA receptor influence its functional responses, which are involved in multiple synaptic processes and neuronal signaling. The structure of the CTD still remains unresolved, which poses challenges toward providing a mechanism for the process of phosphorylation and deciphering the role of each phosphorylation step in causing the resultant conformational behavior. Herein, we utilize smFRET spectroscopy to understand the mechanism of phosphorylation, with the help of strategic point mutations that mimic phosphorylation. Our results reveal that first, phosphorylation at three target sites (S818, S831, and T840) is necessary for the change in the secondary structure of the existing disordered native sequence. Also, the results suggest that the formation of the tertiary structure through electrostatic interaction involving one specific phosphorylation site (S831) stabilizes the structure and renders conformational rigidity.
AB - Phosphorylation at the intracellular C-terminal domain (CTD) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors induces conformational rigidity. Such intracellular alterations to the AMPA receptor influence its functional responses, which are involved in multiple synaptic processes and neuronal signaling. The structure of the CTD still remains unresolved, which poses challenges toward providing a mechanism for the process of phosphorylation and deciphering the role of each phosphorylation step in causing the resultant conformational behavior. Herein, we utilize smFRET spectroscopy to understand the mechanism of phosphorylation, with the help of strategic point mutations that mimic phosphorylation. Our results reveal that first, phosphorylation at three target sites (S818, S831, and T840) is necessary for the change in the secondary structure of the existing disordered native sequence. Also, the results suggest that the formation of the tertiary structure through electrostatic interaction involving one specific phosphorylation site (S831) stabilizes the structure and renders conformational rigidity.
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U2 - 10.1021/acsomega.9b01384
DO - 10.1021/acsomega.9b01384
M3 - Article
AN - SCOPUS:85071905802
SN - 2470-1343
VL - 4
SP - 14211
EP - 14218
JO - ACS Omega
JF - ACS Omega
IS - 10
ER -