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1.A.1.11.26
Two pore Ca2+ > Na+, Li+ or K+ (non-selective for these three monovalen caions) channel protein of 733 aas and 12 TMSs, TPC1 (Guo et al. 2017). The crystal structure of this vacuolar two-pore channel, a homodimer, has been solved (Guo et al. 2015) (Kintzer and Stroud 2016). Activation requires both voltage and cytosolic Ca2+. Ca2+ binding to the cytosolic EF-hand domain triggers conformational changes coupled to the pair of pore-lining inner helices from the first 6-TMS domains, whereas membrane potential only activates the second voltage-sensing domain, the conformational changes of which are coupled to the pair of inner helices from the second 6-TMS domains. Luminal Ca2+ or Ba2+ modulates voltage activation by stabilizing the second voltage-sensing domain in the resting state and shift voltage activation towards more positive potentials. The basis for understanding ion permeation, channel activation, the location of voltage-sensing domains and regulatory ion-binding sites is partially explained by the 3-d structure (Kintzer and Stroud 2016). Only the second Shaker domain senses voltage (Jaƛlan et al. 2016). It has a selectivity filter that is passable by hydrated divalent cations (Demidchik et al. 2018). Dickinson et al. 2022 determined structures at different stages along its activation coordinate. These structures of activation intermediates, when compared with the resting-state structure, portray a mechanism in which the voltage-sensing domain undergoes dilation and in-membrane plane rotation about the gating charge-bearing helix, followed by charge translocation across the charge transfer seal. These structures, in concert with patch-clamp electrophysiology, showed that residues in the pore mouth sense inhibitory Ca2+ and are allosterically coupled to the voltage sensor. These conformational changes provide insight into the mechanism of voltage-sensor domain activation in which activation occurs vectorially over a series of elementary steps (Dickinson et al. 2022).  Inhibition of the Akt/PKB kinase increases Nav1.6-mediated currents and neuronal excitability in CA1 hippocampal pyramidal neurons (Marosi et al. 2022).

Accession Number:Q94KI8
Protein Name:Two pore calcium channel protein 1
Length:733
Molecular Weight:84873.00
Species:Arabidopsis thaliana (Mouse-ear cress) [3702]
Number of TMSs:12
Location1 / Topology2 / Orientation3: Vacuole membrane1 / Multi-pass membrane protein2
Substrate calcium(2+), lithium(1+), sodium(1+), sodium(1+), potassium(1+)

Cross database links:

Structure:
5E1J   5dqq   5TUA   6CX0   6E1K   6E1M   6E1N   6E1P     

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MEDPLIGRDS LGGGGTDRVR RSEAITHGTP FQKAAALVDL AEDGIGLPVE ILDQSSFGES 
61:	ARYYFIFTRL DLIWSLNYFA LLFLNFFEQP LWCEKNPKPS CKDRDYYYLG ELPYLTNAES 
121:	IIYEVITLAI LLVHTFFPIS YEGSRIFWTS RLNLVKVACV VILFVDVLVD FLYLSPLAFD 
181:	FLPFRIAPYV RVIIFILSIR ELRDTLVLLS GMLGTYLNIL ALWMLFLLFA SWIAFVMFED 
241:	TQQGLTVFTS YGATLYQMFI LFTTSNNPDV WIPAYKSSRW SSVFFVLYVL IGVYFVTNLI 
301:	LAVVYDSFKE QLAKQVSGMD QMKRRMLEKA FGLIDSDKNG EIDKNQCIKL FEQLTNYRTL 
361:	PKISKEEFGL IFDELDDTRD FKINKDEFAD LCQAIALRFQ KEEVPSLFEH FPQIYHSALS 
421:	QQLRAFVRSP NFGYAISFIL IINFIAVVVE TTLDIEESSA QKPWQVAEFV FGWIYVLEMA 
481:	LKIYTYGFEN YWREGANRFD FLVTWVIVIG ETATFITPDE NTFFSNGEWI RYLLLARMLR 
541:	LIRLLMNVQR YRAFIATFIT LIPSLMPYLG TIFCVLCIYC SIGVQVFGGL VNAGNKKLFE 
601:	TELAEDDYLL FNFNDYPNGM VTLFNLLVMG NWQVWMESYK DLTGTWWSIT YFVSFYVITI 
661:	LLLLNLVVAF VLEAFFTELD LEEEEKCQGQ DSQEKRNRRR SAGSKSRSQR VDTLLHHMLG 
721:	DELSKPECST SDT