Thumbnail Image
Item

Structural insights on TRPV5 gating by endogenous modulators

Hughes, Taylor E. T.
; 
Pumroy, Ruth A.
; 
Yazici, Aysenur Torun
; ; 
Fluck, Edwin C.
; 
Huynh, Kevin W.
; 
Samanta, Amrita
; 
Molugu, Sudheer K.
; 
Zhou, Z. Hong
; ... show 2 more
Citations
Altmetric:
Genre
Journal article
Date
2018-10-10
Advisor
Committee member
Group
Institute for Computational Molecular Science (Temple University)
Department
Physics
Subject
Cryoelectron microscopy
 Ion transport
Permanent link to this record
http://hdl.handle.net/20.500.12613/8777
Collections
Faculty/Researcher Works
Show all metadata
Files
Thumbnail Image
KasimovaCarnevale-JournalArticle-2018.pdf
Adobe PDF, 2.82 MB
Research Projects
Organizational Units
Journal Issue
DOI
https://doi.org/10.1038/s41467-018-06753-6
Abstract
TRPV5 is a transient receptor potential channel involved in calcium reabsorption. Here we investigate the interaction of two endogenous modulators with TRPV5. Both phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and calmodulin (CaM) have been shown to directly bind to TRPV5 and activate or inactivate the channel, respectively. Using cryo-electron microscopy (cryo-EM), we determined TRPV5 structures in the presence of dioctanoyl PI(4,5)P2 and CaM. The PI(4,5)P2 structure reveals a binding site between the N-linker, S4-S5 linker and S6 helix of TRPV5. These interactions with PI(4,5)P2 induce conformational rearrangements in the lower gate, opening the channel. The CaM structure reveals two TRPV5 C-terminal peptides anchoring a single CaM molecule and that calcium inhibition is mediated through a cation-Ï€ interaction between Lys116 on the C-lobe of calcium-activated CaM and Trp583 at the intracellular gate of TRPV5. Overall, this investigation provides insight into the endogenous modulation of TRPV5, which has the potential to guide drug discovery.
Description
Citation
Hughes, T.E.T., Pumroy, R.A., Yazici, A.T. et al. Structural insights on TRPV5 gating by endogenous modulators. Nat Commun 9, 4198 (2018). https://doi.org/10.1038/s41467-018-06753-6
Citation to related work
Nature Research
Has part
Nature Communications, Vol. 9
ADA compliance
For Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
Embedded videos