Ligand-induced activation of human TRPM2 requires the terminal ribose of ADPR and involves Arg1433 and Tyr1349

The Biochemical Journal
Ralf FliegertAndreas H Guse

Abstract

TRPM2 (transient receptor potential channel, subfamily melastatin, member 2) is a Ca2+-permeable non-selective cation channel activated by the binding of adenosine 5'-diphosphoribose (ADPR) to its cytoplasmic NUDT9H domain (NUDT9 homology domain). Activation of TRPM2 by ADPR downstream of oxidative stress has been implicated in the pathogenesis of many human diseases, rendering TRPM2 an attractive novel target for pharmacological intervention. However, the structural basis underlying this activation is largely unknown. Since ADP (adenosine 5'-diphosphate) alone did not activate or antagonize the channel, we used a chemical biology approach employing synthetic analogues to focus on the role of the ADPR terminal ribose. All novel ADPR derivatives modified in the terminal ribose, including that with the seemingly minor change of methylating the anomeric-OH, abolished agonist activity at TRPM2. Antagonist activity improved as the terminal substituent increasingly resembled the natural ribose, indicating that gating by ADPR might require specific interactions between hydroxyl groups of the terminal ribose and the NUDT9H domain. By mutating amino acid residues of the NUDT9H domain, predicted by modelling and docking to interact with ...Continue Reading

References

Oct 15, 1992·Biochemical and Biophysical Research Communications·L GuidaA De Flora
Aug 1, 1981·Pflügers Archiv : European journal of physiology·O P HamillF J Sigworth
Mar 15, 1993·Biochemical and Biophysical Research Communications·H C LeeA De Flora
Aug 18, 2001·Science·Y SanoK Furuichi
Jul 24, 2002·Biochemistry·Sandra B GabelliL Mario Amzel
Sep 2, 2003·Journal of Molecular Biology·Betty W ShenBarry L Stoddard
Nov 25, 2004·The Journal of Biological Chemistry·Anne-Laure PerraudAndrew M Scharenberg
Dec 1, 2005·The Journal of Biological Chemistry·Andreas GasserAndreas H Guse
Mar 28, 2006·The Journal of Biological Chemistry·Olivera GrubishaJohn M Denu
Jan 26, 2007·American Journal of Physiology. Cell Physiology·Wenyi ZhangBarbara A Miller
Sep 26, 2007·The Journal of General Physiology·John StarkusReinhold Penner
Nov 21, 2007·The Journal of Immunology : Official Journal of the American Association of Immunologists·Santiago Partida-SanchezFrances E Lund
Jul 5, 2008·The Journal of Biological Chemistry·Ben BuelowAndrew M Scharenberg
Apr 18, 2009·Proceedings of the National Academy of Sciences of the United States of America·Jianyang DuLixia Yue
Jun 6, 2009·The Biochemical Journal·Tanja KirchbergerAndreas H Guse
Mar 3, 2010·The Journal of Physiology·John G StarkusReinhold Penner
Jul 28, 2010·The Journal of Biological Chemistry·Wei YangLin-Hua Jiang

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Citations

Apr 20, 2018·Acta Pharmacologica Sinica·Jillian Corinne Belrose, Michael Frederick Jackson
Mar 12, 2020·Molecular Biology and Evolution·Nathaniel J HimmelDaniel N Cox
Apr 14, 2020·The Journal of General Physiology·Wei Lü, Juan Du
Sep 10, 2020·International Journal of Molecular Sciences·Frank J P Kühn
Oct 24, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Peilin YuWei Yang
Dec 10, 2020·Cells·Ivanka JimenezFelipe Simon
Jul 25, 2021·International Journal of Molecular Sciences·Wioletta ZielińskaAlina Grzanka
Jul 1, 2021·The FEBS Journal·Ellen GattkowskiHenning Tidow

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Methods Mentioned

BETA
ion exchange chromatography
transfection
protein assay
pulldown

Software Mentioned

CaBuf
Schrödinger
PyMol
SigmaStat3
SigmaPlot10
R
MS Excel
PatchMaster
GOLD
GraphPad Prism

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