The crystal structure of TRPM2 MHR1/2 domain reveals a conserved Zn2+-binding domain essential for structural integrity and channel activity

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.

Automated summary

Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable channel involved in various physiological processes. ADP-ribose and 2'-deoxy-ADPR can activate TRPM2 by binding to its MHR1/2 domain. A previously unrecognized zinc-binding domain was discovered, which plays a critical role in TRPM2 activation.