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Biochim Biophys Acta Mol Cell Res. 2018 Dec 22. pii: S0167-4889(18)30540-8. doi: 10.1016/j.bbamcr.2018.12.010. [Epub ahead of print]

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

Author information

1
The Hamburg Centre for Ultrafast Imaging & Department of Chemistry, Institute for Biochemistry and Molecular Biology, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany; Department of Biochemistry and Molecular Cell Biology, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany.
2
Department of Biochemistry and Molecular Cell Biology, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany.
3
European Molecular Biology Laboratory Hamburg, Notkestrasse 85, D-22607 Hamburg, Germany.
4
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, United Kingdom.
5
Department of Biochemistry and Molecular Cell Biology, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany. Electronic address: r.fliegert@uke.de.
6
The Hamburg Centre for Ultrafast Imaging & Department of Chemistry, Institute for Biochemistry and Molecular Biology, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany. Electronic address: tidow@chemie.uni-hamburg.de.

Abstract

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.

KEYWORDS:

2′-deoxy-ADPR; Calcium channel; Calmodulin-binding; TRPM2; Temperature sensor

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