6nq2

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Cryo-EM structure of human TPC2 channel in the ligand-bound closed state

Structural highlights

6nq2 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.4Å
Experimental data:Check to display Experimental Data
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TPC2_HUMAN Nicotinic acid adenine dinucleotide phosphate (NAADP) receptor that may function as one of the major voltage-gated Ca(2+) channels (VDCC) across the lysosomal membrane. May be involved in smooth muscle contraction.[1] [2]

Publication Abstract from PubMed

Mammalian two-pore channels (TPCs) regulate the physiological functions of the endolysosome. Here we present cryo-EM structures of human TPC2 (HsTPC2), a phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2)-activated, Na(+) selective channel, in the ligand-bound and apo states. The apo structure captures the closed conformation, while the ligand-bound form features the channel in both open and closed conformations. Combined with functional analysis, these structures provide insights into the mechanism of PI(3,5)P2-regulated gating of TPC2, which is distinct from that of TPC1. Specifically, the endolysosome-specific PI(3,5)P2 binds at the first 6-TM and activates the channel - independently of the membrane potential - by inducing a structural change at the pore-lining inner helix (IS6), which forms a continuous helix in the open state but breaks into two segments at Gly317 in the closed state. Additionally, structural comparison to the voltage-dependent TPC1 structure allowed us to identify Ile551 as being responsible for the loss of voltage dependence in TPC2.

Structural mechanisms of phospholipid activation of the human TPC2 channel.,She J, Zeng W, Guo J, Chen Q, Bai XC, Jiang Y Elife. 2019 Mar 12;8. pii: 45222. doi: 10.7554/eLife.45222. PMID:30860481[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Calcraft PJ, Ruas M, Pan Z, Cheng X, Arredouani A, Hao X, Tang J, Rietdorf K, Teboul L, Chuang KT, Lin P, Xiao R, Wang C, Zhu Y, Lin Y, Wyatt CN, Parrington J, Ma J, Evans AM, Galione A, Zhu MX. NAADP mobilizes calcium from acidic organelles through two-pore channels. Nature. 2009 May 28;459(7246):596-600. doi: 10.1038/nature08030. Epub 2009 Apr, 22. PMID:19387438 doi:http://dx.doi.org/10.1038/nature08030
  2. ↑ Brailoiu E, Churamani D, Cai X, Schrlau MG, Brailoiu GC, Gao X, Hooper R, Boulware MJ, Dun NJ, Marchant JS, Patel S. Essential requirement for two-pore channel 1 in NAADP-mediated calcium signaling. J Cell Biol. 2009 Jul 27;186(2):201-9. doi: 10.1083/jcb.200904073. Epub 2009 Jul , 20. PMID:19620632 doi:http://dx.doi.org/10.1083/jcb.200904073
  3. ↑ She J, Zeng W, Guo J, Chen Q, Bai XC, Jiang Y. Structural mechanisms of phospholipid activation of the human TPC2 channel. Elife. 2019 Mar 12;8. pii: 45222. doi: 10.7554/eLife.45222. PMID:30860481 doi:http://dx.doi.org/10.7554/eLife.45222

Contents


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6nq2, resolution 3.40Å

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