6DJS

Hybrid model of TRPC3 in GDN

Summary for 6DJS

• Entry DOI: 10.2210/pdb6djs/pdb
• Related: 6DJR
• EMDB information: 7940
• Descriptor: Short transient receptor potential channel 3 (1 entity in total)
• Functional Keywords: trp channel, ion channel, membrane protein, cerebellum, moonwalker, transport protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 275135.91

Authors

Sierra-Valdez, F.J.,Azumaya, C.M.,Nakagawa, T.,Cordero-Morales, J.F. (deposition date: 2018-05-26, release date: 2018-08-29, Last modification date: 2024-03-13)

Primary citation

Sierra-Valdez, F.,Azumaya, C.M.,Romero, L.O.,Nakagawa, T.,Cordero-Morales, J.F.
Structure-function analyses of the ion channel TRPC3 reveal that its cytoplasmic domain allosterically modulates channel gating.
J. Biol. Chem., 293:16102-16114, 2018

PubMed Abstract: The transient receptor potential ion channels support Ca 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.

PubMed: 30139744
DOI: 10.1074/jbc.RA118.005066

Experimental method

ELECTRON MICROSCOPY (5.8 Å)