A distinct concerted mechanism of structural dynamism defines activity of human serine protease HtrA3

Acharya, Saujanya; Dutta, Shubhankar; Bose, Kakoli

doi:10.1042/bcj20190706

Cited by 7 publications

(6 citation statements)

References 69 publications

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“…Like HTRA1, the other HTRA family members exhibit conformational plasticity within the catalytic center [51][52][53] , and might be susceptible to a LoopA-directed allosteric lock mechanism akin to HTRA1. This hypothesis was tested by the use of chimeric HTRA2 and HTRA3 proteases containing the engrafted LoopA from HTRA1, which provided high-affinity Fab binding to the chimeras.…”

Section: Discussionmentioning

confidence: 99%

Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration

Gerhardy¹,

Ultsch²,

Tang³

et al. 2022

Nat Commun

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The trimeric serine protease HTRA1 is a genetic risk factor associated with geographic atrophy (GA), a currently untreatable form of age-related macular degeneration. Here, we describe the allosteric inhibition mechanism of HTRA1 by a clinical Fab fragment, currently being evaluated for GA treatment. Using cryo-EM, X-ray crystallography and biochemical assays we identify the exposed LoopA of HTRA1 as the sole Fab epitope, which is approximately 30 Å away from the active site. The cryo-EM structure of the HTRA1:Fab complex in combination with molecular dynamics simulations revealed that Fab binding to LoopA locks HTRA1 in a non-competent conformational state, incapable of supporting catalysis. Moreover, grafting the HTRA1-LoopA epitope onto HTRA2 and HTRA3 transferred the allosteric inhibition mechanism. This suggests a conserved conformational lock mechanism across the HTRA family and a critical role of LoopA for catalysis, which was supported by the reduced activity of HTRA1-3 upon LoopA deletion or perturbation. This study reveals the long-range inhibition mechanism of the clinical Fab and identifies an essential function of the exposed LoopA for activity of HTRA family proteases.

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Section: Discussionmentioning

confidence: 99%

Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration

Gerhardy¹,

Ultsch²,

Tang³

et al. 2022

Nat Commun

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“…Human HTRA3 is a trimer multitasking serine protease related to cell function and pathogenicity. It may serve as a potential therapeutic target ( 9 ). HTRA3 dissolves XIAP and BAX, therefore promoting apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…HtrA Serine Peptidase 3 (HTRA3), which was first reported in 2003, is a protein encoding gene located on chromosome 4p16.1 ( 8 ). HTRA3 protein (expressed in many cell types and organs) has two isomers, which both represent active serine proteases which cleave beta-casein/CSN2 as well as several extracellular matrix (ECM) proteoglycans ( 9 ). Previous studies indicated that HTRA3 inhibits signaling mediated by TGF-beta family proteins possibly indirectly by degradation of these ECM proteoglycans ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

HTRA3 Is a Prognostic Biomarker and Associated With Immune Infiltrates in Gastric Cancer

Sun

Xing

et al. 2020

Front. Oncol.

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HtrA serine peptidase 3 (HTRA3) participates in multiple signal pathways and plays an important regulatory role in various malignancies; however, its role on prognosis and immune infiltrates in gastric cancer (GC) remains unclear. The study investigated HTRA3 expression in tumor tissues and its association with immune infiltrates, and determined its prognostic roles in GC patients. Patients with GC were collected from the cancer genome atlas (TCGA). We compared the expression of HTRA3 in GC and normal gastric mucosa tissues with Wilcoxon rank sum test. And logistic regression was used to evaluate the relationship between HTRA3 and clinicopathological characters. Gene ontology (GO) term analysis, Gene set enrichment analysis (GSEA), and single-sample Gene Set Enrichment Analysis (ssGSEA) was conducted to explain the enrichmental pathways and functions and quantify the extent of immune cells infiltration for HTRA3. Kaplan-Meier analysis and Cox regression were performed to evaluate the correlation between HTRA3 and survival rates. A nomogram, based on Cox multivariate analysis, was used to predict the impact of HTRA3 on prognosis. High HTRA3 expression was significantly correlated with tumor histological type, histological grade, clinical stage, T stage, and TP53 status (P < 0.05). HTRA3-high GC patients had a lower 10-year progression-free interval [PFI; hazard ratio (HR): 1.46; 95% confidence interval (CI): 1.02–2.08; P = 0.038], disease-specific survival (DSS; HR: 1.65; CI: 1.08–2.52; P = 0.021) and overall survival (OS; HR: 1.59; CI: 1.14–2.22; P = 0.006). Multivariate survival analysis showed that HTRA3 was an independent prognostic marker for PFI (HR: 1.456; CI: 1.021–2.078; P = 0.038), DSS (HR: 1.650; CI: 1.079–2.522; P = 0.021) and OS [hazard ratio (HR): 1.590; 95% confidence interval (CI):1.140–2.219; P = 0.006]. The C-indexes and calibration plots of the nomogram based on multivariate analysis indicated an effective predictive performance for GC patients. GSEA showed that High HTRA3 expression may activate NF-κB pathway, YAP1/WWTR1/TAZ pathway, and TGFβ pathway. There was a negative correlation between the HTRA3 expression and the abundances of adaptive immunocytes (T helper cell 17 cells) and a positive correlation with abundances of innate immunocytes (natural killer cells, macrophages etc.). HTRA3 plays a vital role in GC progression and prognosis and could be a moderate biomarker for prediction for survival after gastrectomy.

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“…Supporting information-This article contains supporting information (88)(89)(90). Conflict of interest-The authors declare that they have no conflicts of interest with the contents of this article.…”

Section: Data Availabilitymentioning

confidence: 99%

Activity-based protein profiling reveals active serine proteases that drive malignancy of human ovarian clear cell carcinoma

Mehner¹,

Hockla²,

Coban³

et al. 2022

Journal of Biological Chemistry

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A distinct concerted mechanism of structural dynamism defines activity of human serine protease HtrA3

Cited by 7 publications

References 69 publications

Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration

Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration

HTRA3 Is a Prognostic Biomarker and Associated With Immune Infiltrates in Gastric Cancer

Activity-based protein profiling reveals active serine proteases that drive malignancy of human ovarian clear cell carcinoma

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