6d7l | pdb_00006d7l
Cytoplasmic domain of TRPC3
Structural highlights
Disease[TRPC3_HUMAN] The disease is caused by mutations affecting the gene represented in this entry. Function[TRPC3_HUMAN] Thought to form a receptor-activated non-selective calcium permeant cation channel. Probably is operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors. Activated by diacylglycerol (DAG) in a membrane-delimited fashion, independently of protein kinase C, and by inositol 1,4,5-triphosphate receptors (ITPR) with bound IP3. May also be activated by internal calcium store depletion.[1] [2] [3] [4] Publication Abstract from PubMedThe transient receptor potential ion channels support Ca(2+) 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 A 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. Structure-function analyses of the ion channel TRPC3 reveal that its cytoplasmic domain allosterically modulates channel gating.,Sierra-Valdez F, Azumaya CM, Romero LO, Nakagawa T, Cordero-Morales JF J Biol Chem. 2018 Aug 23. pii: RA118.005066. doi: 10.1074/jbc.RA118.005066. PMID:30139744[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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