Sarco(endo)plasmic Reticulum Calcium ATPase (SERCA) Inhibition by Sarcolipin Is Encoded in Its Luminal Tail

Abstract

Background: Sarcolipin is a regulator of SERCA in skeletal and atrial muscle with inhibitory properties thought to be similar to phospholamban. Results: Residues critical for SERCA inhibition reside in the luminal extension of sarcolipin. Conclusion:The luminal extension of sarcolipin is a distinct and transferrable domain that encodes most of its inhibitory properties. Significance: Sarcolipin and phospholamban use different inhibitory mechanisms to regulate SERCA.

Regulation of the Sarcoplasmic Reticulum Calcium Pump by Divergent Phospholamban Isoforms in Zebrafish

“…There is a high degree of sequence homology in the transmembrane regions of PLN and SLN, suggesting a similar mode of interaction with SERCA (6,7). Although studies have demonstrated that PLN and SLN use distinct structural elements and mechanisms to regulate SERCA (8,9), crystal structures of the SERCA-SLN (10,11) and SERCA-PLN (12) complexes are remarkably similar to one another.…”

“…For the final fit, the remaining rate constants (typically 2-4 rate constants) were allowed to vary to minimize the discrepancy between the experimental data and the kinetic model. The starting points for the kinetic simulations included global fits previously reported for the following: (i) SERCA alone (38), (ii) SERCA in the presence of wild-type PLN (21,36), and (iii) SERCA in the presence of wild-type SLN (8). Errors were calculated as the standard error of the mean based on standard deviations calculated by Dynafit.…”

“…Errors were calculated as the standard error of the mean based on standard deviations calculated by Dynafit. A one-sample t test was used to evaluate the statistical significance of individual rate constants versus previously determined values (8,21,36,38).…”

“…Like PLN, the cytoplasmic domain of SLN is involved in regulating the interaction with SERCA (25,26). However, unlike PLN, much of the inhibitory activity of SLN relies on its unique luminal domain rather than its transmembrane domain alone (8).…”

“…The topology of PLN is organized into three domains as follows: an ␣-helical cytoplasmic domain (residues [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], a linker domain (residues [21][22][23][24][25][26][27][28][29][30], and an ␣-helical transmembrane domain (residues 31-52) (13)(14)(15)(16). The cytoplasmic domain makes a small contribution to SERCA inhibition, yet it has two phosphorylation sites (Ser 16 and Thr 17 ) that play a critical role in the regulation of PLN inhibitory function.…”