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- EMDB-21129: Structure of TRPA1 modified by iodoacetamide, PMAL-C8 -

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Basic information

Entry
Database: EMDB / ID: EMD-21129
TitleStructure of TRPA1 modified by iodoacetamide, PMAL-C8
Map dataFull map
Sample
  • Complex: TRPA1 modified by iodoacetamide, solubilized in PMAL-C8
    • Protein or peptide: Transient receptor potential cation channel subfamily A member 1
Function / homology
Function and homology information


temperature-gated cation channel activity / stereocilium bundle / detection of chemical stimulus involved in sensory perception of pain / thermoception / TRP channels / channel activity / response to pain / cellular response to organic substance / intracellularly gated calcium channel activity / detection of mechanical stimulus involved in sensory perception of pain ...temperature-gated cation channel activity / stereocilium bundle / detection of chemical stimulus involved in sensory perception of pain / thermoception / TRP channels / channel activity / response to pain / cellular response to organic substance / intracellularly gated calcium channel activity / detection of mechanical stimulus involved in sensory perception of pain / monoatomic ion transport / sensory perception of pain / response to cold / response to organic substance / calcium ion transmembrane transport / calcium channel activity / intracellular calcium ion homeostasis / response to organic cyclic compound / cellular response to hydrogen peroxide / protein homotetramerization / cell surface receptor signaling pathway / response to xenobiotic stimulus / identical protein binding / plasma membrane
Similarity search - Function
Ankyrin repeat / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Transient receptor potential cation channel subfamily A member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsZhao J / Lin King JV / Paulsen CE / Cheng Y / Julius D
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R35 NS105038 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM098672 United States
CitationJournal: Nature / Year: 2020
Title: Irritant-evoked activation and calcium modulation of the TRPA1 receptor.
Authors: Jianhua Zhao / John V Lin King / Candice E Paulsen / Yifan Cheng / David Julius /
Abstract: The transient receptor potential ion channel TRPA1 is expressed by primary afferent nerve fibres, in which it functions as a low-threshold sensor for structurally diverse electrophilic irritants, ...The transient receptor potential ion channel TRPA1 is expressed by primary afferent nerve fibres, in which it functions as a low-threshold sensor for structurally diverse electrophilic irritants, including small volatile environmental toxicants and endogenous algogenic lipids. TRPA1 is also a 'receptor-operated' channel whose activation downstream of metabotropic receptors elicits inflammatory pain or itch, making it an attractive target for novel analgesic therapies. However, the mechanisms by which TRPA1 recognizes and responds to electrophiles or cytoplasmic second messengers remain unknown. Here we use strutural studies and electrophysiology to show that electrophiles act through a two-step process in which modification of a highly reactive cysteine residue (C621) promotes reorientation of a cytoplasmic loop to enhance nucleophilicity and modification of a nearby cysteine (C665), thereby stabilizing the loop in an activating configuration. These actions modulate two restrictions controlling ion permeation, including widening of the selectivity filter to enhance calcium permeability and opening of a canonical gate at the cytoplasmic end of the pore. We propose a model to explain functional coupling between electrophile action and these control points. We also characterize a calcium-binding pocket that is highly conserved across TRP channel subtypes and accounts for all aspects of calcium-dependent TRPA1 regulation, including potentiation, desensitization and activation by metabotropic receptors. These findings provide a structural framework for understanding how a broad-spectrum irritant receptor is controlled by endogenous and exogenous agents that elicit or exacerbate pain and itch.
History
DepositionDec 16, 2019-
Header (metadata) releaseJan 15, 2020-
Map releaseMay 6, 2020-
UpdateDec 2, 2020-
Current statusDec 2, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 4
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 4
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6v9x
  • Surface level: 6
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
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Supplemental images

emd_21129.png

Downloads & links

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Map

FileDownload / File: emd_21129.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFull map
Voxel sizeX=Y=Z: 1.2156 Å
Density
Contour LevelBy AUTHOR: 0.1 / Movie #1: 4
Minimum - Maximum-31.670258 - 49.65341
Average (Standard dev.)0.000000101418 (±0.99999845)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 311.1936 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.21560156251.21560156251.2156015625
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z311.194311.194311.194
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ400400400
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-31.67049.6530.000

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Supplemental data

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Mask #1

Fileemd_21129_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 1

Fileemd_21129_half_map_1.map
AnnotationHalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 2

Fileemd_21129_half_map_2.map
AnnotationHalf map 2
Projections & Slices
AxesZYX

Projections

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Histogram (log scale)

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Sample components

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Entire : TRPA1 modified by iodoacetamide, solubilized in PMAL-C8

EntireName: TRPA1 modified by iodoacetamide, solubilized in PMAL-C8
Components
  • Complex: TRPA1 modified by iodoacetamide, solubilized in PMAL-C8
    • Protein or peptide: Transient receptor potential cation channel subfamily A member 1

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Supramolecule #1: TRPA1 modified by iodoacetamide, solubilized in PMAL-C8

SupramoleculeName: TRPA1 modified by iodoacetamide, solubilized in PMAL-C8
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant strain: HEK293F
Molecular weightTheoretical: 400 KDa

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Macromolecule #1: Transient receptor potential cation channel subfamily A member 1

MacromoleculeName: Transient receptor potential cation channel subfamily A member 1
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 127.703586 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MKRSLRKMWR PGEKKEPQGV VYEDVPDDTE DFKESLKVVF EGSAYGLQNF NKQKKLKRCD DMDTFFLHYA AAEGQIELME KITRDSSLE VLHEMDDYGN TPLHCAVEKN QIESVKFLLS RGANPNLRNF NMMAPLHIAV QGMNNEVMKV LLEHRTIDVN L EGENGNTA ...String:
MKRSLRKMWR PGEKKEPQGV VYEDVPDDTE DFKESLKVVF EGSAYGLQNF NKQKKLKRCD DMDTFFLHYA AAEGQIELME KITRDSSLE VLHEMDDYGN TPLHCAVEKN QIESVKFLLS RGANPNLRNF NMMAPLHIAV QGMNNEVMKV LLEHRTIDVN L EGENGNTA VIIACTTNNS EALQILLKKG AKPCKSNKWG CFPIHQAAFS GSKECMEIIL RFGEEHGYSR QLHINFMNNG KA TPLHLAV QNGDLEMIKM CLDNGAQIDP VEKGRCTAIH FAATQGATEI VKLMISSYSG SVDIVNTTDG CHETMLHRAS LFD HHELAD YLISVGADIN KIDSEGRSPL ILATASASWN IVNLLLSKGA QVDIKDNFGR NFLHLTVQQP YGLKNLRPEF MQMQ QIKEL VMDEDNDGCT PLHYACRQGG PGSVNNLLGF NVSIHSKSKD KKSPLHFAAS YGRINTCQRL LQDISDTRLL NEGDL HGMT PLHLAAKNGH DKVVQLLLKK GALFLSDHNG WTALHHASMG GYTQTMKVIL DTNLKCTDRL DEDGNTALHF AAREGH AKA VALLLSHNAD IVLNKQQASF LHLALHNKRK EVVLTIIRSK RWDECLKIFS HNSPGNK(YCM)PI TEMIEYLPEC MKV LLDFCM LHSTEDKSCR DYYIEYNFKY LQCPLEFTKK TPTQDVIYEP LTALNAMVQN NRIELLNHPV CKEYLLMKWL AYGF RAHMM NLGSYCLGLI PMTILVVNIK PGMAFNSTGI INETSDHSEI LDTTNSYLIK TCMILVFLSS IFGYCKEAGQ IFQQK RNYF MDISNVLEWI IYTTGIIFVL PLFVEIPAHL QWQCGAIAVY FYWMNFLLYL QRFENCGIFI VMLEVILKTL LRSTVV FIF LLLAFGLSFY ILLNLQDPFS SPLLSIIQTF SMMLGDINYR ESFLEPYLRN ELAHPVLSFA QLVSFTIFVP IVLMNLL IG LAVGDIADVQ KHASLKRIAM QVELHTSLEK KLPLWFLRKV DQKSTIVYPN KPRSGGMLFH IFCFLFCTGE IRQEIPNA D KSLEMEILKQ KYRLKDLTFL LEKQHELIKL IIQKMEIISE TEDDDSHCSF QDRFKKEQME QRNSRWNTVL RAVKAKTHH LEP

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
GridDetails: unspecified
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI POLARA 300
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 40.0 e/Å2
Experimental equipment
Model: Tecnai Polara / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: PROJECTION MATCHING
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 190112
FSC plot (resolution estimation)

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