Please use this identifier to cite or link to this item: https://doi.org/10.1073/pnas.2115849118
Title: Symmetric activation and modulation of the human calcium-sensing receptor
Authors: Park, J
Zuo, H
Frangaj, A
Fu, Z
Yen, LY
Zhang, Z
Mosyak, L
Slavkovich, VN
Liu, J
Ray, KM
Cao, B
Vallese, F
Geng, Y
Chen, S
Grassucci, R
Dandey, VP
Tan, YZ 
Eng, E
Lee, Y
Kloss, B
Liu, Z
Hendrickson, WA
Potter, CS
Carragher, B
Graziano, J
Conigrave, AD
Frank, J
Clarke, OB
Fan, QR
Keywords: activation mechanism
allosteric modulation
calcium-sensing receptor
cryo-EM structure
symmetry
Calcium
Cryoelectron Microscopy
Gene Expression Regulation
HEK293 Cells
Homeostasis
Humans
Models, Molecular
Protein Conformation
Protein Domains
Receptors, Calcium-Sensing
Signal Transduction
Issue Date: 21-Dec-2021
Publisher: Proceedings of the National Academy of Sciences
Citation: Park, J, Zuo, H, Frangaj, A, Fu, Z, Yen, LY, Zhang, Z, Mosyak, L, Slavkovich, VN, Liu, J, Ray, KM, Cao, B, Vallese, F, Geng, Y, Chen, S, Grassucci, R, Dandey, VP, Tan, YZ, Eng, E, Lee, Y, Kloss, B, Liu, Z, Hendrickson, WA, Potter, CS, Carragher, B, Graziano, J, Conigrave, AD, Frank, J, Clarke, OB, Fan, QR (2021-12-21). Symmetric activation and modulation of the human calcium-sensing receptor. Proceedings of the National Academy of Sciences of the United States of America 118 (51) : e2115849118-. ScholarBank@NUS Repository. https://doi.org/10.1073/pnas.2115849118
Abstract: The human extracellular calcium-sensing (CaS) receptor controls plasma Ca2+ levels and contributes to nutrient-dependent maintenance and metabolism of diverse organs. Allosteric modulation of the CaS receptor corrects disorders of calcium homeostasis. Here, we report the cryogenic-electron microscopy reconstructions of a near–full-length CaS receptor in the absence and presence of allosteric modulators. Activation of the homodimeric CaS receptor requires a break in the transmembrane 6 (TM6) helix of each subunit, which facilitates the formation of a TM6-mediated homodimer interface and expansion of homodimer interactions. This transformation in TM6 occurs without a positive allosteric modulator. Two modulators with opposite functional roles bind to overlapping sites within the transmembrane domain through common interactions, acting to stabilize distinct rotamer conformations of key residues on the TM6 helix. The positive modulator reinforces TM6 distortion and maximizes subunit contact to enhance receptor activity, while the negative modulator strengthens an intact TM6 to dampen receptor function. In both active and inactive states, the receptor displays symmetrical transmembrane conformations that are consistent with its homodimeric assembly.
Source Title: Proceedings of the National Academy of Sciences of the United States of America
URI: https://scholarbank.nus.edu.sg/handle/10635/227196
ISSN: 00278424
10916490
DOI: 10.1073/pnas.2115849118
Appears in Collections:Staff Publications
Elements

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
2021-12-16_Park_ ProceedingsoftheNationalAcademyofSciences.pdfPublished version1.99 MBAdobe PDF

OPEN

NoneView/Download

SCOPUSTM   
Citations

5
checked on Oct 1, 2022

Page view(s)

30
checked on Sep 29, 2022

Download(s)

1
checked on Sep 29, 2022

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.