title: PLEIAD/SIMC1/C5orf25, a novel autolysis regulator for a skeletal-muscle-specific calpain, CAPN3, scaffolds a CAPN3 substrate, CTBP1.
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.
authors.affiliation: Calpain Project, Department of Advanced Science for Biomolecules, Tokyo Metropolitan Institute of Medical Science (IGAKUKEN), 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan. ono-ys@igakuken.or.jp
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Ono
authors.forename: Shun-Ichiro
authors.initials: S
authors.lastname: Iemura
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Novak
authors.forename: Naoko
authors.initials: N
authors.lastname: Doi
authors.forename: Fujiko
authors.initials: F
authors.lastname: Kitamura
authors.forename: Tohru
authors.initials: T
authors.lastname: Natsume
authors.forename: Carol C
authors.initials: CC
authors.lastname: Gregorio
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sorimachi
mesh_terms: D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002154:Calpain / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000201:enzymology / Q000502:physiology; D011485:Protein Binding; D059748:Proteolysis
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009124:Muscle Proteins; C583727:SIMC1 protein, human; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; C105884:CAPN3 protein, human; D002154:Calpain
keywords: NCBI; National Center for Biotechnology Information; YTH; autolysis; calpain; scaffold; skeletal muscle; substrate; yeast two-hybrid