6CV9
Cytoplasmic domain of mTRPC6
Summary for 6CV9
| Entry DOI | 10.2210/pdb6cv9/pdb |
| EMDB information | 7637 |
| Descriptor | Short transient receptor potential channel 6 (1 entity in total) |
| Functional Keywords | ion channel, membrane protein, trp channel, trpc6, focal segmental glomerulosclerosis, transport protein |
| Biological source | Mus musculus (Mouse) |
| Total number of polymer chains | 4 |
| Total formula weight | 386685.50 |
| Authors | Azumaya, C.M.,Sierra-Valdez, F.J.,Cordero-Morales, J.F.,Nakagawa, T. (deposition date: 2018-03-27, release date: 2018-05-23, Last modification date: 2024-03-13) |
| Primary citation | Azumaya, C.M.,Sierra-Valdez, F.,Cordero-Morales, J.F.,Nakagawa, T. Cryo-EM structure of the cytoplasmic domain of murine transient receptor potential cation channel subfamily C member 6 (TRPC6). J. Biol. Chem., 293:10381-10391, 2018 Cited by PubMed Abstract: The kidney maintains the internal milieu by regulating the retention and excretion of proteins, ions, and small molecules. The glomerular podocyte forms the slit diaphragm of the ultrafiltration filter, whose damage leads to progressive kidney failure and focal segmental glomerulosclerosis (FSGS). The canonical transient receptor potential 6 (TRPC6) ion channel is expressed in the podocyte, and mutations in its cytoplasmic domain cause FSGS in humans. evaluation of disease-causing mutations in TRPC6 has revealed that these genetic alterations result in abnormal ion channel gating. However, the mechanism whereby the cytoplasmic domain modulates TRPC6 function is largely unknown. Here, we report a cryo-EM structure of the cytoplasmic domain of murine TRPC6 at 3.8 Å resolution. The cytoplasmic fold of TRPC6 is characterized by an inverted dome-like chamber pierced by four radial horizontal helices that converge into a vertical coiled-coil at the central axis. Unlike other TRP channels, TRPC6 displays a unique domain swap that occurs at the junction of the horizontal helices and coiled-coil. Multiple FSGS mutations converge at the buried interface between the vertical coiled-coil and the ankyrin repeats, which form the dome, suggesting these regions are critical for allosteric gating modulation. This functionally critical interface is a potential target for drug design. Importantly, dysfunction in other family members leads to learning deficits (TRPC1/4/5) and ataxia (TRPC3). Our data provide a structural framework for the mechanistic investigation of the TRPC family. PubMed: 29752403DOI: 10.1074/jbc.RA118.003183 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.8 Å) |
Structure validation
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