ArticleScientific reports2017
HtrA1 activation is driven by an allosteric mechanism of inter-monomer communication.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers, 2 of them syntheses that pooled it.
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Who cites it
21 citing papers in PubMed, 2 syntheses or guidelines pooled it, 29 citations in OpenAlex.
- Exploring the Role of HtrA Family Genes in Cancer: A Systematic Review.Molecular diagnosis & therapy · 2024Pooled it
- Genotype-phenotype correlations of heterozygous HTRA1-related cerebral small vessel disease: case report and systematic review.Neurogenetics · 2021Pooled it
- Gene-Exercise Interactions in Amyloid Metabolism and Clearance: Implications for Alzheimer's Disease.International journal of molecular sciences · 2025Review
- HTRA1-dependent proteolysis induces age-related retinal degeneration and exacerbates choroidal neovascularization.Disease models & mechanisms · 2025Article
- Nonallosteric activation of posttranslational modification enzymes by active site-directed inhibitors.Computational and structural biotechnology journal · 2024Article
- Rational correction of pathogenic conformational defects in HTRA1.Nature communications · 2024Article
- HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species.Nature communications · 2024Article
- Fever-like temperature bursts promote competence development via an HtrA-dependent pathway in Streptococcus pneumoniae.PLoS genetics · 2023Article
- The emerging role of the HTRA1 protease in brain microvascular disease.Frontiers in dementia · 2023Review
- Case report: Heterozygous mutation in HTRA1 causing typical cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy.Frontiers in genetics · 2023Article
- Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration.Nature communications · 2022Article
- Proteomic profiling in cerebral amyloid angiopathy reveals an overlap with CADASIL highlighting accumulation of HTRA1 and its substrates.Acta neuropathologica communications · 2022Article
- Racemization in Post-Translational Modifications Relevance to Protein Aging, Aggregation and Neurodegeneration: Tip of the Iceberg.Symmetry · 2021Article
- Cerebral Small Vessel Disease Related to a Heterozygous Nonsense Mutation in HTRA1.Internal medicine (Tokyo, Japan) · 2020Article
- Molecular structure and the role of high-temperature requirement protein 1 in skeletal disorders and cancers.Cell proliferation · 2020Review
- Late-onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1.Aging cell · 2019Article
- The serine protease HtrA1 cleaves misfolded transforming growth factor β-induced protein (TGFBIp) and induces amyloid formation.The Journal of biological chemistry · 2019Article
- HTRA1 Mutations Identified in Symptomatic Carriers Have the Property of Interfering the Trimer-Dependent Activation Cascade.Frontiers in neurology · 2019Article
- Murine osteoclasts secrete serine protease HtrA1 capable of degrading osteoprotegerin in the bone microenvironment.Communications biology · 2019Article
- Amino-Terminal Processing ofFrontiers in microbiology · 2018Article
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The human protease family HtrA is responsible for preventing protein misfolding and mislocalization, and a key player in several cellular processes. Among these, HtrA1 is implicated in several cancers, cerebrovascular disease and age-related macular degeneration. Currently, HtrA1 activation is not fully characterized and relevant for drug-targeting this protease. Our work provides a mechanistic step-by-step description of HtrA1 activation and regulation. We report that the HtrA1 trimer is regulated by an allosteric mechanism by which monomers relay the activation signal to each other, in a PDZ-domain independent fashion. Notably, we show that inhibitor binding is precluded if HtrA1 monomers cannot communicate with each other. Our study establishes how HtrA1 trimerization plays a fundamental role in proteolytic activity. Moreover, it offers a structural explanation for HtrA1-defective pathologies as well as mechanistic insights into the degradation of complex extracellular fibrils such as tubulin, amyloid beta and tau that belong to the repertoire of HtrA1.
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Registered trials
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.