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Calpain-2 participates in the process of calpain-1 inactivation.

Biosci Rep. 2020 Nov 27;40(11)
Fumiko Shinkai-Ouchi 1 , Mayumi Shindo 2 , Naoko Doi 1 , Shoji Hata 1 , Yasuko Ono 1
Fumiko Shinkai-Ouchi 1 , Mayumi Shindo 2 , Naoko Doi 1 , Shoji Hata 1 , Yasuko Ono 1

[No authors listed]

Author information
  • 1 Calpain Project, Department of Basic Medical Sciences, Tokyo Metropolitan Institute of Medical Science (TMiMS), 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156- 8506, Japan.
  • 2 Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science (TMiMS), 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156- 8506, Japan.

摘要


Calpain-1 and calpain-2 are highly structurally similar isoforms of calpain. The calpains, a family of intracellular cysteine proteases, cleave their substrates at specific sites, thus modifying their properties such as function or activity. These isoforms have long been considered to function in a redundant or complementary manner, as they are both ubiquitously expressed and activated in a Ca2+- dependent manner. However, studies using isoform-specific knockout and knockdown strategies revealed that each calpain species carries out specific functions in vivo. To understand the mechanisms that differentiate calpain-1 and calpain-2, we focused on the efficiency and longevity of each calpain species after activation. Using an in vitro proteolysis assay of troponin T in combination with mass spectrometry, we revealed distinctive aspects of each isoform. Proteolysis mediated by calpain-1 was more sustained, lasting as long as several hours, whereas proteolysis mediated by calpain-2 was quickly blunted. Calpain-1 and calpain-2 also differed from each other in their patterns of autolysis. Calpain-2-specific autolysis sites in its PC1 domain are not cleaved by calpain-1, but calpain-2 cuts calpain-1 at the corresponding position. Moreover, at least in vitro, calpain-1 and calpain-2 do not perform substrate proteolysis in a synergistic manner. On the contrary, calpain-1 activity is suppressed in the presence of calpain-2, possibly because it is cleaved by the latter protein. These results suggest that calpain-2 functions as a down-regulation of calpain-1, a mechanism that may be applicable to other calpain species as well.

KEYWORDS: autolysis, calpains, inhibition mechanism, proteolysis, regulation, substrate specificity