4.6 Article

Role of conserved regulatory loop residues in allosteric propagation of serine protease HtrA2

Journal

Publisher

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2022.01.042

Keywords

HtrA2; Serine protease; Conserved residues; Regulatory loops; Allostery; XIAP

Funding

  1. National Women Bio scientist Young Category by Department of Biotechnology (DBT), Govt. of India [BT/HRD/NBA/37/05/2015]

Ask authors/readers for more resources

High temperature requirement protease A2 (HtrA2) plays important roles in protein quality control and apoptosis regulation. The stability of its active conformation is influenced by the dynamics of the L3 loop, which is mediated by three specific residues. Understanding the regulation of HtrA2 activation may contribute to the development of therapeutic agents.
High temperature requirement protease A2 (HtrA2) is a mitochondrial serine protease that demonstrates multifaceted roles including protein quality control and proapoptotic properties in humans, making it a potential therapeutic target. Current literature suggests involvement of flexible regulatory loops in governing the allosteric propagation within the trimeric HtrA2 ensemble. Here, we have identified three important residues R147, P148 (L3 loop) and F131 (LD loop) surrounding the catalytic-site that play crucial roles in stabilizing HtrA2 active conformation during its multimodal activation. Although mutagenesis of these residues does not affect the structural integrity, it renders the protease inactive by affecting the regulatory inter-subunit PDZ-protease crosstalk. This is further emphasized by the inactivity observed during N-terminal mediated activation of the HtrA2 loop mutants via BIR2 domain of the antiapoptotic protein XIAP. Overall, our results demonstrate the importance of L3 loop dynamics in mediating the inter-molecular allostery via R147-P148 residues. Understanding the on-off switch that regulates HtrA2 activation might help in designing HtrA2 modulators for therapeutic applications.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.6
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available