The sarco(endo)plasmic reticulum calcium ATPase (SERCA) is regulated in a 
tissue-dependent manner via interaction with the short integral membrane 
proteins phospholamban (PLN) and sarcolipin (SLN). Although defects in SERCA 
activity are known to cause heart failure, the regulatory mechanisms imposed by 
PLN and SLN could have clinical implications for both heart and skeletal muscle 
diseases. PLN and SLN have significant sequence homology in their transmembrane 
regions, suggesting a similar mode of binding to SERCA. However, unlike PLN, SLN 
has a conserved C-terminal luminal tail composed of five amino acids 
((27)RSYQY), which may contribute to a distinct SERCA regulatory mechanism. We 
have functionally characterized alanine mutants of the C-terminal tail of SLN 
using co-reconstituted proteoliposomes of SERCA and SLN. We found that Arg(27) 
and Tyr(31) are essential for SLN function. We also tested the effect of a 
truncated variant of SLN (Arg(27)stop) and extended chimeras of PLN with the 
five luminal residues of SLN added to its C terminus. The Arg(27)stop form of 
SLN resulted in loss of function, whereas the PLN chimeras resulted in 
superinhibition with characteristics of both PLN and SLN. Based on our results, 
we propose that the C-terminal tail of SLN is a distinct, essential domain in 
the regulation of SERCA and that the functional properties of the SLN tail can 
be transferred to PLN.