6CV9

Cytoplasmic domain of mTRPC6


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.80 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Cryo-EM structure of the cytoplasmic domain of murine transient receptor potential cation channel subfamily C member 6 (TRPC6).

Azumaya, C.M.Sierra-Valdez, F.Cordero-Morales, J.F.Nakagawa, T.

(2018) J Biol Chem 293: 10381-10391

  • DOI: https://doi.org/10.1074/jbc.RA118.003183
  • Primary Citation of Related Structures:  
    6CV9

  • 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. In vitro 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.


  • Organizational Affiliation

    From the Department of Molecular Physiology and Biophysics.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Short transient receptor potential channel 6
A, B, C, D
842Mus musculusMutation(s): 0 
Gene Names: Trpc6Trp6Trrp6
UniProt
Find proteins for Q61143 (Mus musculus)
Explore Q61143 
Go to UniProtKB:  Q61143
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ61143
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.80 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 
EM Software:
TaskSoftware PackageVersion
MODEL REFINEMENTPHENIX1.13-2998-000
RECONSTRUCTIONRELION2.1

Structure Validation

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Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)United StatesR01HD061543
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesR01GM125629

Revision History  (Full details and data files)

  • Version 1.0: 2018-05-23
    Type: Initial release
  • Version 1.1: 2018-07-11
    Changes: Data collection, Database references
  • Version 1.2: 2019-12-11
    Changes: Author supporting evidence
  • Version 1.3: 2024-03-13
    Changes: Data collection, Database references