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

Abstract

Transient receptor potential melastatin 2 (TRPM2) is a Ca 2+ -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 0 -deoxy-ADPR in a Ca 2+ -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 0 -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 Zn 2+ -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 Zn 2+ -binding domain on TRPM2 activation. Our results provide insight into a conserved motif essential for structural integrity and channel activity.

Calcium’s Role and Signaling in Aging Muscle, Cellular Senescence, and Mineral Interactions

“…For example, TRPM6 and TRPM7 primarily transport magnesium, but also mediate calcium and zinc transduction [101][102][103]. TRPM2, primarily activated by nucleotides such as adenosine diphosphate ribose, oxidative stress, or others in the presence of calcium, contains the conserved Zn 2+ -binding domain that is essential for structural integrity and channel activity [104]. TRPM2 on the membrane of lysosomes can be potentiated by elevated Ca 2+ inducing Zn 2+ release to a toxic level progressing towards apoptosis [105].…”