This study is led by Prof. Wei Yang (Zhejiang University School of Medicine), Dr Cheng Ma (Zhejiang University School of Medicine), Miss Yanping Luo (Zhejiang University School of Medicine) and Miss Congyi Zhang (Zhejiang University School of Medicine).
The evolutionary process of proteins, particularly through amino acid substitutions, is fundamental for species adaptation. Proteins, such as those involved in brain development, oxygen delivery, and ion transportation, undergo complex evolutionary trajectories. For instance, the evolution of hemoglobin from its ancestral form to its current structure involved minimal genetic changes yet significant alterations in function and structure.
Ion channels are ancient membrane proteins, which regulate various physiological processes. TRPM2, an ancient ion channel found across species, plays crucial roles in oxidative stress-related diseases, neutrophil chemotaxis, insulin secretion, and body temperature regulation. TRPM2's tetrameric structure contains specific domains critical for activation by ADP-ribose (ADPR) and calcium ions (Ca2+), with notable differences in activation modes across species.
This study performed a systematic analysis of TRPM2 channels from over 280 species, to understand their evolutionary trajectory in channel activation modes by ADPR and Ca2+. Combining molecular evolution techniques with mutagenesis and patch-clamp recording, the researchers identify three stages of evolution in the activation mode of TRPM2 channels, progressing from simple to intermediate and then to a more complex and coordinated mechanism. A novel gating mode in fish TRPM2 proteins was identified, representing an evolutionary intermediate. This study also points out important permissive changes at a specific position that occurred during the transition from water to land in vertebrates, indicating the origin of the NUDT9-H domain's dependence for channel activation by ADPR.
The researchers suggest that environmental oxygen levels may play a role in facilitating the development of a more precisely regulated activation mechanism for TRPM2 channels. This study could provide insights into the evolution of other ion channels, receptors, or proteins, shedding light on how species adapt to their environments at the protein level.
See the article: Evolutionary trajectory of TRPM2 channel activation by adenosine diphosphate ribose and calcium.
