Replacement of Lys27 by asparagine in the SERCA regulator myoregulin: A Ca2+ affinity modulator or a catalytic activity switch?

Nishadh Rathod, Guadalupe Guerrero-Serna, Howard S Young, L Michel Espinoza-Fonseca

Biochimica et biophysica acta. Molecular cell research 2024 Jan

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Myoregulin (MLN) is a protein that regulates the activity of the sarcoplasmic reticulum Ca2+-ATPase (SERCA) without affecting its affinity for Ca2+. MLN's residue Lys27 is located at a site where other SERCA regulators control Ca2+ affinity. Therefore, we conducted atomistic simulations and ATPase activity experiments to determine whether replacing Lys27 with asparagine, a conserved residue found in various muscle SERCA regulators, would enable MLN to modulate both the Ca2+ affinity and catalytic activity of SERCA. Our findings indicate that replacing Lys27 with Asn significantly enhances the inhibitory potency of MLN, but it does not affect SERCA's affinity for Ca2+. We suggest that the SERCA site modulating Ca2+ affinity also acts as a catalytic activity switch. Therefore, this site is a key element contributing to the functional divergence among homologous SERCA regulators. This study paves the way for future investigations to explore how biological function diverges during the evolution of the SERCA regulator family. Copyright © 2023 Elsevier B.V. All rights reserved.

Citation

Nishadh Rathod, Guadalupe Guerrero-Serna, Howard S Young, L Michel Espinoza-Fonseca. Replacement of Lys27 by asparagine in the SERCA regulator myoregulin: A Ca2+ affinity modulator or a catalytic activity switch? Biochimica et biophysica acta. Molecular cell research. 2024 Jan;1871(1):119613