ArticleProceedings of the National Academy of Sciences of the United States of America2021
Oligomeric assembly regulating mitochondrial HtrA2 function as examined by methyl-TROSY NMR.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 39 citations in OpenAlex.
- Proteostasis of organelles in aging and disease.The FEBS journal · 2026Review
- Anthracycline-induced cardiomyopathy in childhood cancer survivors is associated with gene signatures of mitochondrial dysfunction-a COG ALTE03N1 report.Cardio-oncology (London, England) · 2025Article
- Quality control at the powerhouse: mitochondrial proteostasis dysfunction and disease.Biochemical Society transactions · 2025Article
- Allosteric regulation of proteolytic machines unveiled by the synergy between cryo-EM and solution NMR spectroscopy.The Biochemical journal · 2025Review
- Maintaining the Integral Membrane Proteome: Revisiting the Functional Repertoire of Integral Membrane Proteases.Chembiochem : a European journal of chemical biology · 2025Review
- Structural basis of substrate recognition and allosteric activation of the proapoptotic mitochondrial HtrA2 protease.Nature communications · 2024Article
- Large Chaperone Complexes Through the Lens of Nuclear Magnetic Resonance Spectroscopy.Annual review of biophysics · 2022Review
- Structural basis of protein substrate processing by human mitochondrial high-temperature requirement A2 protease.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- NMR methods for exploring 'dark' states in ligand binding and protein-protein interactions.Progress in nuclear magnetic resonance spectroscopy · 2022Review
- Review
- Review
- Unraveling the Dichotomy of Enigmatic Serine Protease HtrA2.Frontiers in molecular biosciences · 2022Review
- APP deficiency and HTRA2 modulates PrPBBA advances · 2022Article
- Probing allosteric interactions in homo-oligomeric molecular machines using solution NMR spectroscopy.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Structural basis of DegP protease temperature-dependent activation.Science advances · 2021Article
- Targeting PDZ domains as potential treatment for viral infections, neurodegeneration and cancer.Biology direct · 2021Review
- Dissecting the role of interprotomer cooperativity in the activation of oligomeric high-temperature requirement A2 protein.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Competing stress-dependent oligomerization pathways regulate self-assembly of the periplasmic protease-chaperone DegP.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Human High temperature requirement A2 (HtrA2) is a mitochondrial protease chaperone that plays an important role in cellular proteostasis and in regulating cell-signaling events, with aberrant HtrA2 function leading to neurodegeneration and parkinsonian phenotypes. Structural studies of the enzyme have established a trimeric architecture, comprising three identical protomers in which the active sites of each protease domain are sequestered to form a catalytically inactive complex. The mechanism by which enzyme function is regulated is not well understood. Using methyl transverse relaxation optimized spectroscopy (TROSY)-based solution NMR in concert with biochemical assays, a functional HtrA2 oligomerization/binding cycle has been established. In the absence of substrates, HtrA2 exchanges between a heretofore unobserved hexameric conformation and the canonical trimeric structure, with the hexamer showing much weaker affinity toward substrates. Both structures are substrate inaccessible, explaining their low basal activity in the absence of the binding of activator peptide. The binding of the activator peptide to each of the protomers of the trimer occurs with positive cooperativity and induces intrasubunit domain reorientations to expose the catalytic center, leading to increased proteolytic activity. Our data paint a picture of HtrA2 as a finely tuned, stress-protective enzyme whose activity can be modulated both by oligomerization and domain reorientation, with basal levels of catalysis kept low to avoid proteolysis of nontarget proteins.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.