POSSIBLE REGULATION OF THE SKELETAL-MUSCLE RYANODINE RECEPTOR BY A POLYUBIQUITIN BINDING SUBUNIT OF THE 26S PROTEASOME

Proteolytic digestion of ryanodine receptor (RyR) purified from skelet al muscle generated 25 short peptides. The amino acid sequences of two , 'KC5' and 'KC7', were absent from the RyR primary structure deduced by cDNA cloning. The sequence of KC7 corresponded to the N-terminus of the 12 kDa FK506-binding protein, which associates with the RyR and m odulates its Ca2+ release channel (CRC) function. The sequence of KC5 was not similar to any proteins in the databases searched at that time . In the present study, the sequence of KC5 was compared to proteins i n the current Swissprot database release and corresponds most closely to S5a, a proteasome subunit. Since S5a targets the 26S proteasome to polyubiquitinated proteins, and inositol 1,4,5-trisphosphate receptors , a related class of CRC, are down-regulated by a polyubiquitin-depend ent mechanism in hormone stimulated cells, the abundance of RyRs may b e controlled by association with this regulatory subunit. (C) 1998 Aca demic Press.