6v9w | pdb_00006v9w
Structure of TRPA1 (ligand-free) with bound calcium, LMNG
Structural highlights
Disease[TRPA1_HUMAN] Familial episodic pain syndrome with predominantly upper body involvement. The disease is caused by mutations affecting the gene represented in this entry. Function[TRPA1_HUMAN] Receptor-activated non-selective cation channel involved in detection of pain and possibly also in cold perception and inner ear function (PubMed:25389312, PubMed:25855297). Has a central role in the pain response to endogenous inflammatory mediators and to a diverse array of volatile irritants, such as mustard oil, cinnamaldehyde, garlic and acrolein, an irritant from tears gas and vehicule exhaust fumes (PubMed:25389312, PubMed:20547126). Is also activated by menthol (in vitro)(PubMed:25389312). Acts also as an ionotropic cannabinoid receptor by being activated by delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana (PubMed:25389312). May be a component for the mechanosensitive transduction channel of hair cells in inner ear, thereby participating in the perception of sounds. Probably operated by a phosphatidylinositol second messenger system (By similarity).[UniProtKB:Q8BLA8][1] [2] [3] Publication Abstract from PubMedThe 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(1). 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(2). 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. Irritant-evoked activation and calcium modulation of the TRPA1 receptor.,Zhao J, Lin King JV, Paulsen CE, Cheng Y, Julius D Nature. 2020 Jul 8. pii: 10.1038/s41586-020-2480-9. doi:, 10.1038/s41586-020-2480-9. PMID:32641835[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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