Structure–function analyses of the ion channel TRPC3 reveal that its cytoplasmic domain allosterically modulates channel gating

Francisco Sierra-Valdez, Caleigh M. Azumaya, Luis O. Romero, Terunaga Nakagawa, Julio Cordero-Morales

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The transient receptor potential ion channels support Ca2 permeation in many organs, including the heart, brain, and kidney. Genetic mutations in transient receptor potential cation channel subfamily C member 3 (TRPC3) are associated with neurodegenerative diseases, memory loss, and hypertension. To better understand the conformational changes that regulate TRPC3 function, we solved the cryo-EM structures for the full-length human TRPC3 and its cytoplasmic domain (CPD) in the apo state at 5.8- and 4.0-Å resolution, respectively. These structures revealed that the TRPC3 transmembrane domain resembles those of other TRP channels and that the CPD is a stable module involved in channel assembly and gating. We observed the presence of a C-terminal domain swap at the center of the CPD where horizontal helices (HHs) transition into a coiled-coil bundle. Comparison of TRPC3 structures revealed that the HHs can reside in two distinct positions. Electrophysiological analyses disclosed that shortening the length of the C-terminal loop connecting the HH with the TRP helices increases TRPC3 activity and that elongating the length of the loop has the opposite effect. Our findings indicate that the C-terminal loop affects channel gating by altering the allosteric coupling between the cytoplasmic and transmembrane domains. We propose that molecules that target the HH may represent a promising strategy for controlling TRPC3-associated neurological disorders and hypertension.

Original languageEnglish (US)
Pages (from-to)16102-16114
Number of pages13
JournalJournal of Biological Chemistry
Volume293
Issue number41
DOIs
StatePublished - Jan 1 2018

Fingerprint

Neurodegenerative diseases
Ion Channels
Permeation
Brain
Hypertension
Transient Receptor Potential Channels
Data storage equipment
Molecules
Memory Disorders
Nervous System Diseases
Neurodegenerative Diseases
Kidney
Mutation
TRPC3 cation channel

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Structure–function analyses of the ion channel TRPC3 reveal that its cytoplasmic domain allosterically modulates channel gating. / Sierra-Valdez, Francisco; Azumaya, Caleigh M.; Romero, Luis O.; Nakagawa, Terunaga; Cordero-Morales, Julio.

In: Journal of Biological Chemistry, Vol. 293, No. 41, 01.01.2018, p. 16102-16114.

Research output: Contribution to journalArticle

Sierra-Valdez, Francisco ; Azumaya, Caleigh M. ; Romero, Luis O. ; Nakagawa, Terunaga ; Cordero-Morales, Julio. / Structure–function analyses of the ion channel TRPC3 reveal that its cytoplasmic domain allosterically modulates channel gating. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 41. pp. 16102-16114.
@article{d5c6bb61c4144cce9fc543147a353bb8,
title = "Structure–function analyses of the ion channel TRPC3 reveal that its cytoplasmic domain allosterically modulates channel gating",
abstract = "The transient receptor potential ion channels support Ca2 permeation in many organs, including the heart, brain, and kidney. Genetic mutations in transient receptor potential cation channel subfamily C member 3 (TRPC3) are associated with neurodegenerative diseases, memory loss, and hypertension. To better understand the conformational changes that regulate TRPC3 function, we solved the cryo-EM structures for the full-length human TRPC3 and its cytoplasmic domain (CPD) in the apo state at 5.8- and 4.0-{\AA} resolution, respectively. These structures revealed that the TRPC3 transmembrane domain resembles those of other TRP channels and that the CPD is a stable module involved in channel assembly and gating. We observed the presence of a C-terminal domain swap at the center of the CPD where horizontal helices (HHs) transition into a coiled-coil bundle. Comparison of TRPC3 structures revealed that the HHs can reside in two distinct positions. Electrophysiological analyses disclosed that shortening the length of the C-terminal loop connecting the HH with the TRP helices increases TRPC3 activity and that elongating the length of the loop has the opposite effect. Our findings indicate that the C-terminal loop affects channel gating by altering the allosteric coupling between the cytoplasmic and transmembrane domains. We propose that molecules that target the HH may represent a promising strategy for controlling TRPC3-associated neurological disorders and hypertension.",
author = "Francisco Sierra-Valdez and Azumaya, {Caleigh M.} and Romero, {Luis O.} and Terunaga Nakagawa and Julio Cordero-Morales",
year = "2018",
month = "1",
day = "1",
doi = "10.1074/jbc.RA118.005066",
language = "English (US)",
volume = "293",
pages = "16102--16114",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "41",

}

TY - JOUR

T1 - Structure–function analyses of the ion channel TRPC3 reveal that its cytoplasmic domain allosterically modulates channel gating

AU - Sierra-Valdez, Francisco

AU - Azumaya, Caleigh M.

AU - Romero, Luis O.

AU - Nakagawa, Terunaga

AU - Cordero-Morales, Julio

PY - 2018/1/1

Y1 - 2018/1/1

N2 - The transient receptor potential ion channels support Ca2 permeation in many organs, including the heart, brain, and kidney. Genetic mutations in transient receptor potential cation channel subfamily C member 3 (TRPC3) are associated with neurodegenerative diseases, memory loss, and hypertension. To better understand the conformational changes that regulate TRPC3 function, we solved the cryo-EM structures for the full-length human TRPC3 and its cytoplasmic domain (CPD) in the apo state at 5.8- and 4.0-Å resolution, respectively. These structures revealed that the TRPC3 transmembrane domain resembles those of other TRP channels and that the CPD is a stable module involved in channel assembly and gating. We observed the presence of a C-terminal domain swap at the center of the CPD where horizontal helices (HHs) transition into a coiled-coil bundle. Comparison of TRPC3 structures revealed that the HHs can reside in two distinct positions. Electrophysiological analyses disclosed that shortening the length of the C-terminal loop connecting the HH with the TRP helices increases TRPC3 activity and that elongating the length of the loop has the opposite effect. Our findings indicate that the C-terminal loop affects channel gating by altering the allosteric coupling between the cytoplasmic and transmembrane domains. We propose that molecules that target the HH may represent a promising strategy for controlling TRPC3-associated neurological disorders and hypertension.

AB - The transient receptor potential ion channels support Ca2 permeation in many organs, including the heart, brain, and kidney. Genetic mutations in transient receptor potential cation channel subfamily C member 3 (TRPC3) are associated with neurodegenerative diseases, memory loss, and hypertension. To better understand the conformational changes that regulate TRPC3 function, we solved the cryo-EM structures for the full-length human TRPC3 and its cytoplasmic domain (CPD) in the apo state at 5.8- and 4.0-Å resolution, respectively. These structures revealed that the TRPC3 transmembrane domain resembles those of other TRP channels and that the CPD is a stable module involved in channel assembly and gating. We observed the presence of a C-terminal domain swap at the center of the CPD where horizontal helices (HHs) transition into a coiled-coil bundle. Comparison of TRPC3 structures revealed that the HHs can reside in two distinct positions. Electrophysiological analyses disclosed that shortening the length of the C-terminal loop connecting the HH with the TRP helices increases TRPC3 activity and that elongating the length of the loop has the opposite effect. Our findings indicate that the C-terminal loop affects channel gating by altering the allosteric coupling between the cytoplasmic and transmembrane domains. We propose that molecules that target the HH may represent a promising strategy for controlling TRPC3-associated neurological disorders and hypertension.

UR - http://www.scopus.com/inward/record.url?scp=85054894578&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054894578&partnerID=8YFLogxK

U2 - 10.1074/jbc.RA118.005066

DO - 10.1074/jbc.RA118.005066

M3 - Article

C2 - 30139744

AN - SCOPUS:85054894578

VL - 293

SP - 16102

EP - 16114

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 41

ER -