Abstract
CAPN3/p94/calpain-3 is a skeletal-muscle-specific member of the calpain protease family. Multiple muscle cell functions have been reported for CAPN3, and mutations in this protease cause limb-girdle muscular dystrophy type 2A. Little is known about the molecular mechanisms that allow CAPN3 to be so multifunctional. One hypothesis is that the very rapid and exhaustive autolytic activity of CAPN3 needs to be suppressed by dynamic molecular interactions for specific periods of time. The previously identified interaction between CAPN3 and connectin/titin, a giant molecule in muscle sarcomeres, supports this assumption; however, the regulatory mechanisms of non-sarcomere-associated CAPN3 are unknown. Here, we report that a novel CAPN3-binding protein, PLEIAD [Platform element for inhibition of autolytic degradation; originally called SIMC1/C5orf25 (SUMO-interacting motif containing protein 1/chromosome 5open reading frame 25)], suppresses the protease activity of CAPN3. Database analyses showed that PLEIAD homologs, like CAPN3 homologs, are evolutionarily conserved in vertebrates. Furthermore, we found that PLEIAD also interacts with CTBP1 (C-terminal binding protein 1), a transcriptional co-regulator, and CTBP1 is proteolyzed in COS7 cells expressing CAPN3. The identified cleavage sites in CTBP1 suggested that it undergoes functional modification upon its proteolysis by CAPN3, as well as by conventional calpains. These results indicate that PLEIAD can shift its major function from CAPN3 suppression to CAPN3-substrate recruitment, depending on the cellular context. Taken together, our data suggest that PLEIAD is a novel regulatory scaffold for CAPN3, as reflected in its name.
Highlights
IntroductionCAPN3 ( called p94 or calpain-3) is an skm (skeletal muscle)-specific cysteine protease belonging to the calpain super family (EC 3.4.22.18, clan CA, family C2).[1] The calpains are intracellular Ca2+− requiring cysteine proteases
CAPN3 is an skm-specific cysteine protease belonging to the calpain super family (EC 3.4.22.18, clan CA, family C2).[1]
1),[30,31] which is a good substrate for calpains, including CAPN3. These results suggest that SIMC1/C5orf[25] is a suppressor for CAPN3 but, at the same time, scaffolds CAPN3 to direct and regulate its substrate-proteolyzing activity
Summary
CAPN3 ( called p94 or calpain-3) is an skm (skeletal muscle)-specific cysteine protease belonging to the calpain super family (EC 3.4.22.18, clan CA, family C2).[1] The calpains are intracellular Ca2+− requiring cysteine proteases. Many studies have shown that proteolysis by calpain has a modulatory effect on the functions of the substrate proteins.[2,3,4,5,6] calpain is considered to be a modulator protease rather than a degrading protease such as proteasomal and lysosomal proteases.[7]. A surprising finding was that CAPN3 localizes to triads, where it plays an important role as a structural component and not as a protease.[19]
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