Key Points
-
Several lines of evidence have implicated the high temperature requirement A (HTRA) family of homooligomeric Ser proteases in protein quality control.
-
HTRA proteases are implicated in bacterial virulence and stress response, photosynthesis in plants, and proliferation, migration and cell fate in mammals.
-
HTRA proteases share common principles of activation with classic Ser proteases such as trypsin, chymotrypsin and elastase. However, their unique architecture, including carboxy-terminal PDZ (postsynaptic density of 95 kDa, Discs large and zonula occludens 1) domains, is responsible for a remarkable structural and functional plasticity that allows cells to rapidly respond to the presence of misfolded or mislocalized polypeptides.
-
The activity of HTRA proteases is tightly regulated by their switching on and off by peptides that bind to the PDZ domains. Activation is usually reversible and can involve a change in oligomeric state.
-
The PDZ domains of HTRA proteases are involved in a great variety of functions, including allosteric activation, cooperativity, processivity, activation by oligomerization, cellular localization (including lipid binding) and sensing of protein-folding stress.
Abstract
Controlled proteolysis underlies a vast diversity of protective and regulatory processes that are of key importance to cell fate. The unique molecular architecture of the widely conserved high temperature requirement A (HTRA) proteases has evolved to mediate critical aspects of ATP-independent protein quality control. The simple combination of a classic Ser protease domain and a carboxy-terminal peptide-binding domain produces cellular factors of remarkable structural and functional plasticity that allow cells to rapidly respond to the presence of misfolded or mislocalized polypeptides.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Page, M. J. & Di Cera, E. Evolution of peptidase diversity. J. Biol. Chem. 283, 30010–30014 (2008).
Clausen, T., Southan, C. & Ehrmann, M. The HtrA family of proteases. Implications for protein composition and cell fate. Mol. Cell 10, 443–455 (2002).
Krojer, T. et al. Structural basis for the regulated protease and chaperone function of DegP. Nature 453, 885–890 (2008). Provides structural and biochemical evidence that DegP is regulated by substrate binding and changes in its oligomeric state. Also shows that periplasmic assembly intermediates of outer-membrane proteins are captured within the cavity of large oligomeric DegP particles.
Huesgen, P. F., Schuhmann, H. & Adamska, I. Deg/HtrA proteases as components of a network for photosystem II quality control in chloroplasts and cyanobacteria. Res. Microbiol. 160, 726–732 (2009).
Chien, J. et al. Serine protease HtrA1 associates with microtubules and inhibits cell migration. Mol. Cell. Biol. 29, 4177–4187 (2009).
Milner, J. M., Patel, A. & Rowan, A. D. Emerging roles of serine proteinases in tissue turnover in arthritis. Arthritis Rheum. 58, 3644–3656 (2008).
Chien, J., Campioni, M., Shridhar, V. & Baldi, A. HtrA serine proteases as potential therapeutic targets in cancer. Curr. Cancer Drug Targets 9, 451–468 (2009).
Hara, K. et al. Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N. Engl. J. Med. 360, 1729–1739 (2009). Links missense mutations in the HTRA1 gene to cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) and altered TGFβ signalling.
Coleman, H. R., Chan, C. C., Ferris, F. L. 3rd & Chew, E. Y. Age-related macular degeneration. Lancet 372, 1835–1845 (2008).
Vande Walle, L., Lamkanfi, M. & Vandenabeele, P. The mitochondrial serine protease HtrA2/Omi: an overview. Cell Death Differ. 15, 453–460 (2008).
Grau, S. et al. Implications of the serine protease HtrA1 in amyloid precursor protein processing. Proc. Natl Acad. Sci. USA 102, 6021–6026 (2005).
García-Lorenzo, M., Sjödin, A., Jansson, S. & Funk, C. Protease gene families in Populus and Arabidopsis. BMC Plant Biol. 6, 30 (2006).
Kapri-Pardes, E., Naveh, L. & Adam, Z. The thylakoid lumen protease Deg1 is involved in the repair of photosystem II from photoinhibition in Arabidopsis. Plant Cell 19, 1039–1047 (2007). Shows that Deg1 protease cleaves lumen-exposed loops of the photodamaged D1 protein in chloroplasts of A. thaliana.
An, E., Sen, S., Park, S. K., Gordish-Dressman, H. & Hathout, Y. Identification of novel substrates for the serine protease HTRA1 in the human RPE secretome. Invest. Ophthalmol. Vis. Sci. 51, 3379–3386 (2010).
Moisoi, N. et al. Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response. Cell Death Differ. 16, 449–464 (2009).
Oka, C. et al. HtrA1 serine protease inhibits signaling mediated by Tgfβ family proteins. Development 131, 1041–1053 (2004).
Hou, J., Clemmons, D. R. & Smeekens, S. Expression and characterization of a serine protease that preferentially cleaves insulin-like growth factor binding protein-5. J. Cell Biochem. 94, 470–484 (2005).
Spiess, C., Beil, A. & Ehrmann, M. A temperature-dependent switch from chaperone to protease in a widely conserved heat shock protein. Cell 97, 339–347 (1999). First report of a protease that performs the antagonistic functions of protein repair and degradation.
Jiang, J. et al. Activation of DegP chaperone-protease via formation of large cage-like oligomers upon binding to substrate proteins. Proc. Natl Acad. Sci. USA 105, 11939–11944 (2008).
Shen, Q. T. et al. Bowl-shaped oligomeric structures on membranes as DegP's new functional forms in protein quality control. Proc. Natl Acad. Sci. USA 106, 4858–4863 (2009).
Isaac, D. D., Pinkner, J. S., Hultgren, S. J. & Silhavy, T. J. The extracytoplasmic adaptor protein CpxP is degraded with substrate by DegP. Proc. Natl Acad. Sci. USA 102, 17775–17779 (2005).
Spiess, C. et al. Biochemical characterization and mass spectrometric disulfide bond mapping of periplasmic α-amylase MalS of Escherichia coli. J. Biol. Chem. 272, 22125–22133 (1997).
Iwanczyk, J. et al. Role of the PDZ domains in Escherichia coli DegP protein. J. Bacteriol. 189, 3176–3186 (2007).
Padmanabhan, N. et al. The yeast HtrA orthologue Ynm3 is a protease with chaperone activity that aids survival under heat stress. Mol. Biol. Cell 20, 68–77 (2009).
Huston, W. M. et al. The temperature activated HtrA protease from pathogen Chlamydia trachomatis acts as both a chaperone and protease at 37 °C. FEBS Lett. 581, 3382–3386 (2007).
Sun, X. et al. The thylakoid protease Deg1 is involved in photosystem-II assembly in Arabidopsis thaliana. Plant J. 62, 240–249 (2010).
Chaba, R., Grigorova, I., Flynn, J., Baker, T. & Gross, C. Design principles of the proteolytic cascade governing the σE-mediated envelope stress response in Escherichia coli: keys to graded, buffered and rapid signal transduction. Genes Dev. 21, 124–136 (2007).
Walsh, N. P., Alba, B. M., Bose, B., Gross, C. A. & Sauer, R. T. OMP peptide signals initiate the envelope-stress response by activating DegS protease via relief of inhibition mediated by its PDZ domain. Cell 113, 61–71 (2003). Demonstrates that the C termini of outer-membrane proteins activate the σE pathway by binding the PDZ domain of DegS to trigger activation of the protease and its subsequent cleavage of RseA.
Kolmar, H., Waller, P. & Sauer, R. The DegP and DegQ periplasmic endoproteases of Escherichia coli: specificity for cleavage sites and substrate conformation. J. Bacteriol. 178, 5925–5929 (1996).
Huston, W. M. Bacterial proteases from the intracellular vacuole niche; protease conservation and adaptation for pathogenic advantage. FEMS Immunol. Med. Microbiol. 59, 1–10 (2010).
Ingmer, H. & Brondsted, L. Proteases in bacterial pathogenesis. Res. Microbiol. 160, 704–710 (2009).
Baud, C. et al. Role of DegP for two-partner secretion in Bordetella. Mol. Microbiol. 74, 315–329 (2009).
Biswas, S. & Biswas, I. Role of HtrA in surface protein expression and biofilm formation by Streptococcus mutans. Infect. Immun. 73, 6923–6934 (2005).
Hoy, B. et al. Helicobacter pylori HtrA is a new secreted virulence factor that cleaves E-cadherin to disrupt intercellular adhesion. EMBO Rep. 11, 798–804 (2010). Shows that H. pylori HtrA is a secreted protein that promotes virulence by disrupting the epithelial barrier, allowing entry of the pathogen into host cells.
Itzhaki, H., Naveh, L., Lindahl, M., Cook, M. & Adam, Z. Identification and characterization of DegP, a serine protease associated with the luminal side of the thylakoid membrane. J. Biol. Chem. 273, 7094–7098 (1998).
Sun, X. et al. The stromal chloroplast Deg7 protease participates in the repair of photosystem II after photoinhibition in Arabidopsis. Plant Physiol. 152, 1263–1273 (2010).
Sun, X. et al. Formation of DEG5 and DEG8 complexes and their involvement in the degradation of photodamaged photosystem II reaction center D1 protein in Arabidopsis. Plant Cell 19, 1347–1361 (2007).
Zumbrunn, J. & Trueb, B. Primary structure of a putative serine protease specific for IGF-binding proteins. FEBS Lett. 398, 187–192 (1996).
Chien, J. et al. Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity. J. Clin. Invest. 116, 1994–2004 (2006). Demonstrates that the low levels of HTRA1 frequently observed in cancer cells correlate with resistance to chemotherapy.
Baldi, A. et al. The HtrA1 serine protease is down-regulated during human melanoma progression and represses growth of metastatic melanoma cells. Oncogene 21, 6684–6688 (2002).
Launay, S. et al. HtrA1-dependent proteolysis of TGFβ controls both neuronal maturation and developmental survival. Cell Death Differ. 15, 1408–1416 (2008).
Campioni, M. et al. The serine protease HtrA1 specifically interacts and degrades the tuberous sclerosis complex 2 protein. Mol. Cancer Res. 8, 1248–1260 (2010).
Grau, S. et al. The role of human HtrA1 in arthritic disease. J. Biol. Chem. 281, 6124–6129 (2006).
Tsuchiya, A. et al. Expression of mouse HtrA1 serine protease in normal bone and cartilage and its upregulation in joint cartilage damaged by experimental arthritis. Bone 37, 323–336 (2005).
Faccio, L. et al. Characterization of a novel human serine protease that has extensive homology to bacterial heat shock endoprotease HtrA and is regulated by kidney ischemia. J. Biol. Chem. 275, 2581–2588 (2000).
Winklhofer, K. F. & Haass, C. Mitochondrial dysfunction in Parkinson's disease. Biochim. Biophys. Acta 1802, 29–44 (2010).
Fadeel, B. & Grzybowska, E. HAX-1: a multifunctional protein with emerging roles in human disease. Biochim. Biophys. Acta 1790, 1139–1148 (2009).
Cilenti, L. et al. Regulation of HAX-1 anti-apoptotic protein by Omi/HtrA2 protease during cell death. J. Biol. Chem. 279, 50295–50301 (2004).
Chao, J. R. et al. Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons. Nature 452, 98–102 (2008). Finds that the interaction of HAX1 with HTRA2 induces processing of HTRA2 by PARL protease, preventing the accumulation of activated BAX at the outer mitochondrial membrane.
Li, B. et al. Omi/HtrA2 is a positive regulator of autophagy that facilitates the degradation of mutant proteins involved in neurodegenerative diseases. Cell Death Differ. 17, 1773–1784 (2010).
Gray, C. W. et al. Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response. Eur. J. Biochem. 267, 5699–5710 (2000).
Huttunen, H. J. et al. HtrA2 regulates β-amyloid precursor protein (APP) metabolism through endoplasmic reticulum-associated degradation. J. Biol. Chem. 282, 28285–28295 (2007).
Park, H. J. et al. β-amyloid precursor protein is a direct cleavage target of HtrA2 serine protease. Implications for the physiological function of HtrA2 in the mitochondria. J. Biol. Chem. 281, 34277–34287 (2006).
Tocharus, J. et al. Developmentally regulated expression of mouse HtrA3 and its role as an inhibitor of TGFβ signaling. Dev. Growth Differ. 46, 257–274 (2004).
Nie, G., Findlay, J. K. & Salamonsen, L. A. Identification of novel endometrial targets for contraception. Contraception 71, 272–281 (2005).
Bowden, M. A. et al. High-temperature requirement factor A3 (Htra3): a novel serine protease and its potential role in ovarian function and ovarian cancers. Mol. Cell. Endocrinol. 327, 13–18 (2010).
Bowden, M. A., Di Nezza-Cossens, L. A., Jobling, T., Salamonsen, L. A. & Nie, G. Serine proteases HTRA1 and HTRA3 are down-regulated with increasing grades of human endometrial cancer. Gynecol. Oncol. 103, 253–260 (2006).
Narkiewicz, J. et al. Expression of human HtrA1, HtrA2, HtrA3 and TGFβ1 genes in primary endometrial cancer. Oncol. Rep. 21, 1529–1537 (2009).
Beleford, D. et al. Methylation induced gene silencing of HtrA3 in smoking-related lung cancer. Clin. Cancer Res. 16, 398–409 (2010).
Beleford, D., Rattan, R., Chien, J. & Shridhar, V. High temperature requirement A3 (HtrA3) promotes etoposide- and cisplatin-induced cytotoxicity in lung cancer cell lines. J. Biol. Chem. 285, 12011–12027 (2010).
Sheng, M. & Sala, C. PDZ domains and the organization of supramolecular complexes. Annu. Rev. Neurosci. 24, 1–29 (2001).
Wilken, C., Kitzing, K., Kurzbauer, R., Ehrmann, M. & Clausen, T. Crystal structure of the DegS stress sensor: how a PDZ domain recognizes misfolded protein and activates a protease domain. Cell 117, 483–494 (2004). Structures of the inactive and active conformations of DegS reveal the molecular mechanism of DegS activation by stress-signalling peptides during the UPR.
Li, W. et al. Structural insights into the pro-apoptotic function of mitochondrial serine protease HtrA2/Omi. Nature Struct. Biol. 9, 436–441 (2002).
Truebestein, L. et al. Substrate induced remodeling of the active site regulates HtrA1 activity. Nature Struct. Mol. Biol. 6 Feb 2011 (doi:10.1038/nsmb.2013).
Doyle, D. A. et al. Crystal structures of a complexed and peptide-free membrane protein-binding domain: molecular basis of peptide recognition by PDZ. Cell 85, 1067–1076 (1996).
Sakarya, O. et al. Evolutionary expansion and specialization of the PDZ domains. Mol. Biol. Evol. 27, 1058–1069 (2010).
Pereira, P. J. et al. Human β-tryptase is a ring-like tetramer with active sites facing a central pore. Nature 392, 306–311 (1998).
Huber, R. & Bode, W. Structural basis of the activation and action of trypsin. Acc. Chemi. Res. 11, 114–122 (1978).
Friedrich, R. et al. Staphylocoagulase is a prototype for the mechanism of cofactor-induced zymogen activation. Nature 425, 535–539 (2003).
Bode, W. & Huber, R. Induction of the bovine trypsinogen–trypsin transition by peptides sequentially similar to the N-terminus of trypsin. FEBS Lett. 68, 231–236 (1976). First demonstration and structural characterization of the allosteric activation of a monomeric protein, trypsin, and the archetype for physiologically relevant modulation of trypsin-like Ser protease function.
Bode, W., Schwager, P. & Huber, R. The transition of bovine trypsinogen to a trypsin-like state upon strong ligand binding. The refined crystal structures of the bovine trypsinogen–pancreatic trypsin inhibitor complex and of its ternary complex with Ile–Val at 1.9 Å resolution. J. Mol. Biol. 118, 99–112 (1978).
Bode, W. et al. The refined 1.9 Å crystal structure of human α-thrombin: interaction with D-Phe-Pro-Arg chloromethylketone and significance of the Tyr-Pro-Pro-Trp insertion segment. EMBO J. 8, 3467–3475 (1989).
Fuentes-Prior, P. et al. Structural basis for the anticoagulant activity of the thrombin–thrombomodulin complex. Nature 404, 518–525 (2000).
Lechtenberg, B. C., Johnson, D. J., Freund, S. M. & Huntington, J. A. NMR resonance assignments of thrombin reveal the conformational and dynamic effects of ligation. Proc. Natl Acad. Sci. USA 107, 14087–14092 (2010).
Hasenbein, S. et al. Conversion of a regulatory into a degradative protease. J. Mol. Biol. 397, 957–966 (2010).
Merdanovic, M. et al. Determinants of structural and functional plasticity of a widely conserved protease chaperone complex. Nature Struct. Mol. Biol. 17, 837–843 (2010).
Krojer, T., Sawa, J., Huber, R. & Clausen, T. HtrA proteases have a conserved activation mechanism that can be triggered by distinct molecular cues. Nature Struct. Mol. Biol. 17, 844–852 (2010).
Hasselblatt, H. et al. Regulation of the σE stress response by DegS: how the PDZ domain keeps the protease inactive in the resting state and allows integration of different OMP-derived stress signals upon folding stress. Genes Dev. 21, 2659–2670 (2007).
Sohn, J., Grant, R. A. & Sauer, R. T. OMP peptides activate the DegS stress-sensor protease by a relief of inhibition mechanism. Structure 17, 1411–1421 (2009).
Krojer, T., Garrido-Franco, M., Huber, R., Ehrmann, M. & Clausen, T. Crystal structure of DegP (HtrA) reveals a new protease-chaperone machine. Nature 416, 455–459 (2002).
Meltzer, M. et al. Allosteric activation of HtrA protease DegP by stress signals during bacterial protein quality control. Angew. Chem. Int. Ed. Engl. 47, 1332–1334 (2008).
Mohamedmohaideen, N. N. et al. Structure and function of the virulence-associated high-temperature requirement A of Mycobacterium tuberculosis. Biochemistry 47, 6092–6102 (2008).
Krojer, T. et al. Interplay of PDZ and protease domain of DegP ensures efficient elimination of misfolded proteins. Proc. Natl Acad. Sci. USA 105, 7702–7707 (2008).
Zupkovitz, G. et al. Negative and positive regulation of gene expression by mouse histone deacetylase 1. Mol. Cell. Biol. 26, 7913–7928 (2006).
Kaji, K., Nichols, J. & Hendrich, B. Mbd3, a component of the NuRD co-repressor complex, is required for development of pluripotent cells. Development 134, 1123–1132 (2007).
Hauske, P. et al. Peptidic small molecule activators of the stress sensor DegS. Mol. BioSyst. 5, 980–985 (2009).
Hauske, P. et al. Selectivity profiling of DegP substrates and inhibitors. Bioorg. Med. Chem. 17, 2920–2924 (2009).
Cilenti, L. et al. Characterization of a novel and specific inhibitor for the pro-apoptotic protease Omi/HtrA2. J. Biol. Chem. 278, 11489–11494 (2003).
Baell, J. B. & Holloway, G. A. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J. Med. Chem. 53, 2719–2740 (2010).
Klupsch, K. & Downward, J. The protease inhibitor Ucf-101 induces cellular responses independently of its known target, HtrA2/Omi. Cell Death Differ. 13, 2157–2159 (2006).
Groll, M., Huber, R. & Moroder, L. The persisting challenge of selective and specific proteasome inhibition. J. Pept. Sci. 15, 58–66 (2009).
Zhang, Y. et al. Inhibition of Wnt signaling by Dishevelled PDZ peptides. Nature Chem. Biol. 5, 217–219 (2009).
Hammond, M. C., Harris, B. Z., Lim, W. A. & Bartlett, P. A. β strand peptidomimetics as potent PDZ domain ligands. Chem. Biol. 13, 1247–1251 (2006).
Fujii, N. et al. An antagonist of dishevelled protein–protein interaction suppresses β-catenin-dependent tumor cell growth. Cancer Res. 67, 573–579 (2007).
Lowman, H. B. et al. Molecular mimics of insulin-like growth factor 1 (IGF-1) for inhibiting IGF-1: IGF-binding protein interactions. Biochemistry 37, 8870–8878 (1998).
Zhu, Y. F. et al. Quinoline-carboxylic acids are potent inhibitors that inhibit the binding of insulin-like growth factor (IGF) to IGF-binding proteins. Bioorg. Med. Chem. Lett. 13, 1931–1934 (2003).
Chen, C. et al. Discovery of a series of nonpeptide small molecules that inhibit the binding of insulin-like growth factor (IGF) to IGF-binding proteins. J. Med. Chem. 44, 4001–4010 (2001).
Kar, G., Keskin, O., Gursoy, A. & Nussinov, R. Allostery and population shift in drug discovery. Curr. Opin. Pharmacol. 10, 715–722 (2010).
Hardy, J. A. & Wells, J. A. Searching for new allosteric sites in enzymes. Curr. Opin. Struct. Biol. 14, 706–715 (2004).
Ganesan, R., Eigenbrot, C. & Kirchhofer, D. Structural and mechanistic insight into how antibodies inhibit serine proteases. Biochem. J. 430, 179–189 (2010).
Acknowledgements
M.E. was supported by the Deutsche Forschungsgemeinschaft and T.C. by the Fonds zur Förderung der wissenschaftlichen Forschung, Austria, (I 235-B09) in the frame of the ERA-NET NEURON. The Research Institute of Molecular Pathology (IMP) is funded by Boehringer Ingelheim.
Author information
Authors and Affiliations
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
Glossary
- Ser protease
-
An enzyme that hydrolyses peptide bonds using an active site Ser residue as a nucleophile.
- Periplasm
-
A cellular compartment of Gram-negative bacteria that is located between the cytoplasmic and the outer membranes.
- β-augmentation
-
The binding of a peptide ligand as an additional β-strand to an existing β-sheet.
- Catalytic triad
-
In a catalytic triad, the reactivity of the catalytic Ser residue is modulated by two other polar side chains, typically a His and an Asp residue, that determine its nucleophilic character.
- Oxyanion hole
-
During protein cleavage, an intermediate occurs that has a negatively charged carbonyl oxygen. This oxyanion is stabilized by two hydrogen bonds in the oxyanion hole of the protease, which is an amide nitrogen cradle formed by residues preceding the catalytic Ser residue.
- Substrate-specificity pocket
-
The S1 substrate specificity pocket accommodates the side chain of the residue preceding the scissile bond of the substrate, and is one important determinant of specificity.
- Allostery and cooperativity
-
The interaction of binding sites at a distance is termed allostery. It may lead to activation or inhibition by cooperativity between ligands when a ligand bound at one site affects the affinity of another site for its ligand by inducing transitions between distinct conformational states.
- Disorder–order transition
-
Structural elements of proteins can be present in multiple statically and/or dynamically disordered conformations that, in the extreme case, cannot be traced by X-ray crystallography. Disorder of the ligand recognition site impedes enzymatic activity, and ligand binding or other, for example allosteric, signals induce a unique ordered conformation and activity.
- Hill coefficient
-
The Hill coefficient quantifies the cooperativity of ligand binding by an allosteric protein and indicates the minimal number of interacting binding sites. A Hill coefficient of 1 indicates independent binding even when ligands are bound to different binding sites, and a coefficient of >1 reflects positive cooperativity.
- Constitutive activity
-
Refers to an enzyme that is constantly active even in the absence of activating ligands. Constitutive activity can be a phenotype of mutations that affect regulation, causing conformational changes that abolish the need for activation.
- CpG island
-
A genomic region that contains a high content of cytosine (C) and guanine (G) dinucleotides (the 'p' refers to the phosphodiester bond linking the two bases). CpG islands are found in many mammalian promoters, and unlike scattered CpGs throughout the genome, which are usually hypermethylated, promoter CpG islands are normally hypomethylated.
Rights and permissions
About this article
Cite this article
Clausen, T., Kaiser, M., Huber, R. et al. HTRA proteases: regulated proteolysis in protein quality control. Nat Rev Mol Cell Biol 12, 152–162 (2011). https://doi.org/10.1038/nrm3065
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrm3065
This article is cited by
-
HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species
Nature Communications (2024)
-
Protease-independent control of parthanatos by HtrA2/Omi
Cellular and Molecular Life Sciences (2023)
-
Proteomic profiling in cerebral amyloid angiopathy reveals an overlap with CADASIL highlighting accumulation of HTRA1 and its substrates
Acta Neuropathologica Communications (2022)
-
Identification of the potential biological target molecules related to primary open-angle glaucoma
BMC Ophthalmology (2022)
-
Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration
Nature Communications (2022)