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PLEIAD/SIMC1/C5orf25, a novel autolysis regulator for a skeletal-muscle-specific calpain, CAPN3, scaffolds a CAPN3 substrate, CTBP1. | LitMetric

AI Article Synopsis

  • - CAPN3 is a key enzyme in skeletal muscle function and is linked to limb-girdle muscular dystrophy type 2A due to mutations, but how it performs multiple roles at a molecular level is still unclear.
  • - A new protein called PLEIAD has been discovered that inhibits CAPN3's protease activity and changes its function based on the cellular environment, indicating it serves as a regulatory scaffold for CAPN3.
  • - In addition to regulating CAPN3, PLEIAD also interacts with another protein, CTBP1, which is affected by CAPN3's activity, suggesting a more complex interplay between these molecules in muscle cells.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576862PMC
http://dx.doi.org/10.1016/j.jmb.2013.05.009DOI Listing

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