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Structure paper

TitleIrritant-evoked activation and calcium modulation of the TRPA1 receptor.
Journal, issue, pagesNature, Vol. 585, Issue 7823, Page 141-145, Year 2020
Publish dateJul 8, 2020
AuthorsJianhua Zhao / John V Lin King / Candice E Paulsen / Yifan Cheng / David Julius /
PubMed AbstractThe 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.
External linksNature / PubMed:32641835 / PubMed Central
MethodsEM (single particle)
Resolution2.6 - 5.9 Å
Structure data

21127

6v9v

EMDB-21127, PDB-6v9v:
Structure of TRPA1 modified by Bodipy-iodoacetamide with bound calcium, LMNG
Method: EM (single particle) / Resolution: 2.6 Å

21128

6v9w

EMDB-21128, PDB-6v9w:
Structure of TRPA1 (ligand-free) with bound calcium, LMNG
Method: EM (single particle) / Resolution: 3.1 Å

21129

6v9x

EMDB-21129, PDB-6v9x:
Structure of TRPA1 modified by iodoacetamide, PMAL-C8
Method: EM (single particle) / Resolution: 3.3 Å

21130

6v9y

EMDB-21130, PDB-6v9y:
Structure of TRPA1 bound with A-967079, PMAL-C8
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-21131:
Structure of TRPA1 treated with A-967079 (class 2), PMAL-C8
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-21537:
TRPA1 (ligand-free and calcium-free) in PMAL-C8, class 1
Method: EM (single particle) / Resolution: 5.9 Å

EMDB-21538:
Structure of TRPA1 (ligand-free and calcium-free), PMAL-C8, class 2
Method: EM (single particle) / Resolution: 4.3 Å

Chemicals

ChemComp-QT4:
~{N}-[[2,2-bis(fluoranyl)-10,12-dimethyl-1,3-diaza-2$l^{4}-boratricyclo[7.3.0.0^{3,7}]dodeca-4,6,9,11-tetraen-4-yl]methyl]ethanamide

ChemComp-CA:
Unknown entry

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / transient receptor potential subfamily A member 1 / Membrane protein / Transient receptor potential cation channel subfamily A member 1

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Oct 5, 2021. Nobel Prize for mechanically activated and temperature-gated ion channels

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External links:The Nobel Prize in Physiology or Medicine 2021 - NobelPrize.org / Structure data by Ardem Patapoutian / Structure data by David Julius

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