Elucidating the role of GRIM-19 as a substrate and allosteric activator of pro-apoptotic serine protease HtrA2

Author:

Kummari Raghupathi12,Dutta Shubhankar1,Patil Shubhangi1,Mudrale Snehal Pandav1,Bose Kakoli12ORCID

Affiliation:

1. Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India

2. Homi Bhabha National Institute, BARC Training School Complex, Anushaktinagar, Mumbai 400094, India

Abstract

HtrA2 (high-temperature requirement A2) and GRIM-19 (gene associated with retinoic and interferon-induced mortality 19 protein) are involved in various biological functions with their deregulation leading to multiple diseases. Although it is known that the interaction between GRIM-19 with HtrA2 promotes the pro-apoptotic activity of the latter, the mechanistic details remained elusive till date. Moreover, designing allosteric modulators of HtrA2 remains obscure due to lack of adequate information on the mode of interaction with its natural substrates cum binding partners. Therefore, in this study, we have unfolded the interaction between HtrA2 and GRIM-19 so as to understand its subsequent functional repercussions. Using in silico analyses and biochemical assays, we identified the region in GRIM-19 that is involved in protein–protein interaction with HtrA2. Furthermore, we have presented a comprehensive illustration of HtrA2's cleavage site specificity. Quantitative analysis using enzyme kinetics underscored the role of GRIM-19 in significant allosteric activation of HtrA2. Overall, this is an extensive study that not only defines HtrA2–GRIM-19 interaction, but also creates a framework for developing strategies toward allosteric regulation of HtrA2 for future therapeutic interventions.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry

Cited by 4 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Mitochondrial quality control proteases and their modulation for cancer therapy;Medicinal Research Reviews;2022-10-08

2. Regulation of Metabolism by Mitochondrial MUL1 E3 Ubiquitin Ligase;Frontiers in Cell and Developmental Biology;2022-06-29

3. Unraveling the Dichotomy of Enigmatic Serine Protease HtrA2;Frontiers in Molecular Biosciences;2022-02-03

4. Protein Purification by Affinity Chromatography;Textbook on Cloning, Expression and Purification of Recombinant Proteins;2022

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