The crystal structure of TRPM2 MHR1/2 domain reveals a conserved Zn2+ -binding domain essential for structural integrity and channel activity
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The crystal structure of TRPM2 MHR1/2 domain reveals a conserved Zn2+ -binding domain essential for structural integrity and channel activity. / Sander, Simon; Pick, Jelena; Gattkowski, Ellen; Fliegert, Ralf; Tidow, Henning.
In: PROTEIN SCI, Vol. 31, No. 6, e4320, 06.2022.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - The crystal structure of TRPM2 MHR1/2 domain reveals a conserved Zn2+ -binding domain essential for structural integrity and channel activity
AU - Sander, Simon
AU - Pick, Jelena
AU - Gattkowski, Ellen
AU - Fliegert, Ralf
AU - Tidow, Henning
N1 - © 2022 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.
PY - 2022/6
Y1 - 2022/6
N2 - Transient receptor potential melastatin 2 (TRPM2) is a Ca2+ -permeable, nonselective cation channel involved in diverse physiological processes such as immune response, apoptosis, and body temperature sensing. TRPM2 is activated by ADP-ribose (ADPR) and 2'-deoxy-ADPR in a Ca2+ -dependent manner. While two distinct binding sites exist for ADPR that exert different functions dependent on the species, the involvement of either binding site regarding the superagonistic effect of 2'-deoxy-ADPR is not clear yet. Here, we report the crystal structure of the MHR1/2 domain of TRPM2 from zebrafish (Danio rerio), and show that both ligands bind to this domain and activate the channel. We identified a so far unrecognized Zn2+ -binding domain that was not resolved in previous cryo-EM structures and that is conserved in most TRPM channels. In combination with patch clamp experiments we comprehensively characterize the effect of the Zn2+ -binding domain on TRPM2 activation. Our results provide insight into a conserved motif essential for structural integrity and channel activity.
AB - Transient receptor potential melastatin 2 (TRPM2) is a Ca2+ -permeable, nonselective cation channel involved in diverse physiological processes such as immune response, apoptosis, and body temperature sensing. TRPM2 is activated by ADP-ribose (ADPR) and 2'-deoxy-ADPR in a Ca2+ -dependent manner. While two distinct binding sites exist for ADPR that exert different functions dependent on the species, the involvement of either binding site regarding the superagonistic effect of 2'-deoxy-ADPR is not clear yet. Here, we report the crystal structure of the MHR1/2 domain of TRPM2 from zebrafish (Danio rerio), and show that both ligands bind to this domain and activate the channel. We identified a so far unrecognized Zn2+ -binding domain that was not resolved in previous cryo-EM structures and that is conserved in most TRPM channels. In combination with patch clamp experiments we comprehensively characterize the effect of the Zn2+ -binding domain on TRPM2 activation. Our results provide insight into a conserved motif essential for structural integrity and channel activity.
KW - Adenosine Diphosphate Ribose/chemistry
KW - Animals
KW - Calcium/metabolism
KW - TRPM Cation Channels/chemistry
KW - Zebrafish/metabolism
KW - Zinc/metabolism
U2 - 10.1002/pro.4320
DO - 10.1002/pro.4320
M3 - SCORING: Journal article
C2 - 35634784
VL - 31
JO - PROTEIN SCI
JF - PROTEIN SCI
SN - 0961-8368
IS - 6
M1 - e4320
ER -
