Novel CaM-binding motif in its NudT9H domain contributes to temperature sensitivity of TRPM2

TRPM2 is a non-selective, Ca2+-permeable cation channel, which plays a role in cell death but also contributes to diverse immune cell functions. In addition, TRPM2 contributes to the control of body temperature and is involved in perception of non-noxious heat and thermotaxis. TRPM2 is regulated by...

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Published in:Biochimica et biophysica acta. Molecular cell research 2019-07, Vol.1866 (7), p.1162-1170
Main Authors: Gattkowski, Ellen, Johnsen, Anke, Bauche, Andreas, Möckl, Franziska, Kulow, Frederike, Garcia Alai, Maria, Rutherford, Trevor J., Fliegert, Ralf, Tidow, Henning
Format: Article
Language:English
Subjects:
2′-deoxy-ADPR
Amino Acid Motifs
Calcium channel
Calmodulin-binding
HEK293 Cells
Hot Temperature
Humans
Protein Domains
Protein Stability
Temperature sensor
TRPM Cation Channels - chemistry
TRPM Cation Channels - genetics
TRPM Cation Channels - metabolism
TRPM2
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Summary:TRPM2 is a non-selective, Ca2+-permeable cation channel, which plays a role in cell death but also contributes to diverse immune cell functions. In addition, TRPM2 contributes to the control of body temperature and is involved in perception of non-noxious heat and thermotaxis. TRPM2 is regulated by many factors including Ca2+, ADPR, 2′-deoxy-ADPR, Ca2+-CaM, and temperature. However, the molecular basis for the temperature sensitivity of TRPM2 as well as the interplay between the regulatory factors is still not understood. Here we identify a novel CaM-binding site in the unique NudT9H domain of TRPM2. Using a multipronged biophysical approach we show that binding of Ca2+-CaM to this site occurs upon partial unfolding at temperatures >35 °C and prevents further thermal destabilization. In combination with patch-clamp measurements of full-length TRPM2 our results suggest a role of this CaM-binding site in the temperature sensitivity of TRPM2. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech •Identification of a novel CaM-binding site in the NudT9H domain of TRPM2•CaM acts as thermo-stabilizer for the isolated NudT9H domain•CaM binding has an effect on the temperature-dependence of ADPR induced current and activation of TRPM2 by 2′-deoxy-ADPR•Results suggest a role of this CaM-binding site in the temperature sensitivity of TRPM2.
ISSN:0167-4889
1879-2596
DOI:10.1016/j.bbamcr.2018.12.010