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Papers of the Week

Papers: 23 Mar 2024 - 29 Mar 2024

2024 Mar 21

Sci Rep




Experimental and computational evidence that Calpain-10 binds to the carboxy terminus of Na1.2 and Na1.6.


Arratia LM, Bermudes-Contreras JD, Juarez-Monroy JA, Romero-Macías EA, Luna-Rojas JC, López-Hidalgo M, Vega AV, Zamorano-Carrillo A


Voltage-gated sodium channels (Na) are pivotal proteins responsible for initiating and transmitting action potentials. Emerging evidence suggests that proteolytic cleavage of sodium channels by calpains is pivotal in diverse physiological scenarios, including ischemia, brain injury, and neuropathic pain associated with diabetes. Despite this significance, the precise mechanism by which calpains recognize sodium channels, especially given the multiple calpain isoforms expressed in neurons, remains elusive. In this work, we show the interaction of Calpain-10 with Na’s C-terminus through a yeast 2-hybrid assay screening of a mouse brain cDNA library and in vitro by GST-pulldown. Later, we also obtained a structural and dynamic hypothesis of this interaction by modeling, docking, and molecular dynamics simulation. These results indicate that Calpain-10 interacts differentially with the C-terminus of Na1.2 and Na1.6. Calpain-10 interacts with Na1.2 through domains III and T in a stable manner. In contrast, its interaction with Na1.6 involves domains II and III, which could promote proteolysis through the Cys-catalytic site and C2 motifs.