8WPN

Cryo-EM structure of the human TRPC4 in lipid nanodiscs

Summary for 8WPN

• Entry DOI: 10.2210/pdb8wpn/pdb
• EMDB information: 37720
• Descriptor: Short transient receptor potential channel 4, CHOLESTEROL HEMISUCCINATE, ZINC ION, ... (5 entities in total)
• Functional Keywords: transient receptor potential, metal transport
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 425596.32

Authors

Won, J.,Jeong, H.,Lee, H.H. (deposition date: 2023-10-10, release date: 2024-10-16, Last modification date: 2025-03-05)

Primary citation

Won, J.,Kim, J.,Kim, J.,Ko, J.,Park, C.H.,Jeong, B.,Lee, S.E.,Jeong, H.,Kim, S.H.,Park, H.,So, I.,Lee, H.H.
Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel.
Nat.Struct.Mol.Biol., 32:326-338, 2025

PubMed Abstract: Transient receptor potential (TRP) ion channels have a crucial role as cellular sensors, mediating diverse physical and chemical stimuli. The formation of heteromeric structures expands the functionality of TRP channels; however, their molecular architecture remains largely unknown. Here we present the cryo-electron microscopy structures of the human TRPC1/TRPC4 heteromer in the apo and antagonist-bound states, both consisting of one TRPC1 subunit and three TRPC4 subunits. The heteromer structure reveals a distinct ion-conduction pathway, including an asymmetrically constricted selectivity filter and an asymmetric lower gate, primarily attributed to the incorporation of TRPC1. Through a structure-guided electrophysiological assay, we show that both the selectivity filter and the lower part of the S6 helix participate in deciding overall preference for permeating monovalent cations. Moreover, we reveal that the introduction of one lysine residue of TRPC1 into the tetrameric central cavity is enough to render one of the most important functional consequences of TRPC heteromerization: reduced calcium permeability. Our results establish a framework for addressing the structure-function relationship of the heteromeric TRP channels.

PubMed: 39478185
DOI: 10.1038/s41594-024-01408-1

Experimental method

ELECTRON MICROSCOPY (2.82 Å)