PLEIAD/SIMC1/C5orf25, a Novel Autolysis Regulator for a Skeletal-Muscle-Specific Calpain, CAPN3, Scaffolds a CAPN3 Substrate, CTBP1

JOURNAL OF MOLECULAR BIOLOGY

卷:425

Article

Ono, Yasuko^1,2  Iemura, Shun-ichiro^1,3  Novak, Stefanie M.²  Doi, Naoko¹  Kitamura, Fujiko¹  Natsume, Tohru³  Gregorio, Carol C.²  Sorimachi, Hiroyuki¹ 

[1] Tokyo Metropolitan Inst Med Sci IGAKUKEN, Dept Adv Sci Biomol, Calpain Project, Setagaya Ku, Tokyo 1568506, Japan

[2] Univ Arizona, Tucson, AZ 85724 USA

[3] Natl Inst Adv Ind Sci & Technol, Biol Informat Res Ctr, Kohtoh Ku, Tokyo 1350064, Japan

关键词: calpain;    skeletal muscle;    autolysis;    scaffold;    substrate;   

DOI  :  10.1016/j.jmb.2013.05.009

来源: Elsevier

【 摘 要 】

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 5 open 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. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.

【 授权许可】

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