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1.A.4.2.8
The noxious heat (>52°C)-sensitive vanilloid-like receptor cation selective channel, TRPV2. Ca2+-dependent desensitization of TRPV2 channels is mediated by hydrolysis of phosphatidylinositol 4,5-bisphosphate (Mercado et al., 2010).  Deleting the first N-terminal 74 residues preceding the ankyrin repeat domain (ARD) shows a key role for this region in targeting the protein to the membrane. Co-translational insertion of the membrane-embedded region occurs with the TM1-TM4 and TM5-TM6 regions assembling as independent folding domains. ARD is not required for TM domain insertion into the membrane (Doñate-Macian et al. 2015).  The TRPV2 structure has been solved at 4 Å resolution by cryoEM (Zubcevic et al. 2016). Formation of a physical complex between mouse TRPV2 (GRC) and the mouse RGA protein promotes cell surface expression of TRPV2 (Stokes et al. 2005). The role of Ca2+ infllux via TRPV1 in cell death and survival related to cancer has been evaluated (Zhai et al. 2020). A helix-turn-helix motif for high temperature dependence of TRPV2 has been identified (Liu and Qin 2021). As noted above, TRPV2 is a ligand-operated temperature sensor. Zhang et al. 2022 combined calcium imaging and patch-clamp electrophysiology with cryo-EM to explore how TRPV2 activity is modulated by the phytocannabinoid Δ9-tetrahydrocannabiorcol (C16) and by probenecid. C16 and probenecid act in concert to stimulate TRPV2 responses including histamine release from mast cells. Each ligand causes distinct conformational changes in TRPV2. Although the binding for probenecid remains elusive, C16 associates within the vanilloid pocket. As such, the C16 binding location is distinct from that of cannabidiol, partially overlapping with the binding site of the TRPV2 inhibitor piperlongumine (Zhang et al. 2022). The cation-permeable TRPV2 channel is important for cardiac and immune cell function (Gochman et al. 2023). Cannabidiol (CBD), a non-psychoactive cannabinoid of clinical relevance, is one of the few molecules known to activate TRPV2. Using the patch-clamp technique, Gochman et al. 2023 discovered that CBD can sensitize current responses of the rat TRPV2 channel to the synthetic agonist 2-aminoethoxydiphenyl borate (2-APB) by over two orders of magnitude, without sensitizing channels to activation by moderate (40°C) heat. Using cryo-EM, Gochman et al. 2023 uncovered a new small-molecule binding site in the pore domain of rTRPV2 in addition to a nearby CBD site.  Intrinsically disordered regions in TRPV2 mediate protein-protein interactions (Sanganna Gari et al. 2023).

Accession Number:Q9Y5S1
Protein Name:TRPV2 aka VRL-1
Length:764
Molecular Weight:85981.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:6
Location1 / Topology2 / Orientation3: Cell membrane1 / Multi-pass membrane protein2
Substrate inorganic cation, calcium(2+)

Cross database links:

RefSeq: NP_057197.2   
Entrez Gene ID: 51393   
Pfam: PF00023   
OMIM: 606676  gene
KEGG: hsa:51393   

Gene Ontology

GO:0005887 C:integral to plasma membrane
GO:0042470 C:melanosome
GO:0005262 F:calcium channel activity
GO:0006816 P:calcium ion transport
GO:0007600 P:sensory perception

References (7)

[1] “A capsaicin-receptor homologue with a high threshold for noxious heat.”  Caterina M.J.et.al.   10201375
[2] “Complete sequencing and characterization of 21,243 full-length human cDNAs.”  Ota T.et.al.   14702039
[3] “DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage.”  Zody M.C.et.al.   16625196
[4] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[5] “Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes.”  Chi A.et.al.   17081065
[6] “Automated phosphoproteome analysis for cultured cancer cells by two-dimensional nanoLC-MS using a calcined titania/C18 biphasic column.”  Imami K.et.al.   18187866
[7] “Crystal structure of the human TRPV2 channel ankyrin repeat domain.”  McCleverty C.J.et.al.   16882997
Structure:
2F37     

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MTSPSSSPVF RLETLDGGQE DGSEADRGKL DFGSGLPPME SQFQGEDRKF APQIRVNLNY 
61:	RKGTGASQPD PNRFDRDRLF NAVSRGVPED LAGLPEYLSK TSKYLTDSEY TEGSTGKTCL 
121:	MKAVLNLKDG VNACILPLLQ IDRDSGNPQP LVNAQCTDDY YRGHSALHIA IEKRSLQCVK 
181:	LLVENGANVH ARACGRFFQK GQGTCFYFGE LPLSLAACTK QWDVVSYLLE NPHQPASLQA 
241:	TDSQGNTVLH ALVMISDNSA ENIALVTSMY DGLLQAGARL CPTVQLEDIR NLQDLTPLKL 
301:	AAKEGKIEIF RHILQREFSG LSHLSRKFTE WCYGPVRVSL YDLASVDSCE ENSVLEIIAF 
361:	HCKSPHRHRM VVLEPLNKLL QAKWDLLIPK FFLNFLCNLI YMFIFTAVAY HQPTLKKQAA 
421:	PHLKAEVGNS MLLTGHILIL LGGIYLLVGQ LWYFWRRHVF IWISFIDSYF EILFLFQALL 
481:	TVVSQVLCFL AIEWYLPLLV SALVLGWLNL LYYTRGFQHT GIYSVMIQKV ILRDLLRFLL 
541:	IYLVFLFGFA VALVSLSQEA WRPEAPTGPN ATESVQPMEG QEDEGNGAQY RGILEASLEL 
601:	FKFTIGMGEL AFQEQLHFRG MVLLLLLAYV LLTYILLLNM LIALMSETVN SVATDSWSIW 
661:	KLQKAISVLE MENGYWWCRK KQRAGVMLTV GTKPDGSPDE RWCFRVEEVN WASWEQTLPT 
721:	LCEDPSGAGV PRTLENPVLA SPPKEDEDGA SEENYVPVQL LQSN