Volume 31, No 4, Apr 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 4, April 2021: 433-449

ORIGINAL ARTICLES

Ttm50 facilitates calpain activation by anchoring it to calcium stores and increasing its sensitivity to calcium

Elsayed Metwally^1,2,3 , Guoli Zhao^1,4,5 , Qifu Wang¹ , Yong Q. Zhang^1,2,*

¹State Key Laboratory for Molecular and Developmental Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
²International College, University of Chinese Academy of Sciences, Beijing 10080, China
³Present address: Department of Cytology and Histology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
⁴Present address: F. M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA
⁵Present address: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
These authors contributed equally: Elsayed Metwally, Guoli Zhao Correspondence: Yong Q. Zhang(yqzhang@genetics.ac.cn)

Calcium-dependent proteolytic calpains are implicated in a variety of physiological processes, as well as pathologies associated with calcium overload. However, the mechanism by which calpain is activated remains elusive since intracellular calcium levels under physiological conditions do not reach the high concentration range required to trigger calpain activation. From a candidate screening using the abundance of the calpain target glutamate receptor GluRIIA at the Drosophila neuromuscular junction as a readout, we uncovered that calpain activity was inhibited upon knockdown of Ttm50, a subunit of the Tim23 complex known to be involved in the import of proteins across the mitochondrial inner membrane. Unexpectedly, Ttm50 and calpain are co-localized at calcium stores Golgi and endoplasmic reticulum (ER), and Ttm50 interacts with calpain via its C-terminal domain. This interaction is required for calpain localization at Golgi/ER, and increases calcium sensitivity of calpain by roughly an order of magnitude. Our findings reveal the regulation of calpain activation by Ttm50, and shed new light on calpain-associated pathologies.

https://doi.org/10.1038/s41422-020-0388-4

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