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Structural and functional analysis of HtrA1 and its subdomains.

Eigenbrot C, Ultsch M, Lipari MT, Moran P, Lin SJ, Ganesan R, Quan C, Tom J, Sandoval W, van Lookeren Campagne M, Kirchhofer D
Structure 20 1040-50 (2012)
Related entries: 3tjn, 3tjq

Cited: 53 times
EuropePMC logo PMID: 22578544

Abstract

The homotrimeric human serine protease HtrA1 is homologous to bacterial HtrA proteases regarding the trypsin-like catalytic and PDZ domains but differs by the presence of an N-terminal domain with IGFBP and Kazal homology. The crystal structures and SAXS analysis presented herein reveal the rare tandem of IGFBP- and Kazal-like modules, a protease active site that adopts a competent conformation in the absence of substrate or inhibitor and a model for the intact protein in solution. Highly sensitive enzymatic assays and binding studies demonstrate that the N-terminal tandem has no apparent effect on protease activity, and in accordance with the structure-based predictions, neither the IGFBP- nor Kazal-like module retains the function of their prototype proteins. Our structures of the unliganded HtrA1 active site suggest two-state equilibrium and a "conformational selection" model, in which substrate binds to the active conformer.

Articles - 3tjo mentioned but not cited (4)

  1. Structural and Functional Analysis of Human HtrA3 Protease and Its Subdomains. Glaza P, Osipiuk J, Wenta T, Zurawa-Janicka D, Jarzab M, Lesner A, Banecki B, Skorko-Glonek J, Joachimiak A, Lipinska B. PLoS One 10 e0131142 (2015)
  2. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)
  3. Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration. Gerhardy S, Ultsch M, Tang W, Green E, Holden JK, Li W, Estevez A, Arthur C, Tom I, Rohou A, Kirchhofer D. Nat Commun 13 5222 (2022)
  4. research-article Genetically proxied HTRA1 protease activity and circulating levels independently predict risk of ischemic stroke and coronary artery disease. Dichgans M, Malik R, Beaufort N, Tanaka K, Georgakis M, He Y, Koido M, Terao C, Anderson C, Kamatani Y. Res Sq rs.3.rs-3523612 (2023)


Reviews citing this publication (9)

  1. Features of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. Nozaki H, Nishizawa M, Onodera O. Stroke 45 3447-3453 (2014)
  2. The emerging roles of HTRA1 in musculoskeletal disease. Tiaden AN, Richards PJ. Am J Pathol 182 1482-1488 (2013)
  3. Surface loops of trypsin-like serine proteases as determinants of function. Goettig P, Brandstetter H, Magdolen V. Biochimie 166 52-76 (2019)
  4. Insulin-Like Growth Factor-1 (IGF-1) and Its Monitoring in Medical Diagnostic and in Sports. Bailes J, Soloviev M. Biomolecules 11 217 (2021)
  5. Molecular structure and the role of high-temperature requirement protein 1 in skeletal disorders and cancers. Li Y, Yuan J, Rothzerg E, Wu X, Xu H, Zhu S, Xu J. Cell Prolif 53 e12746 (2020)
  6. Are apolipoprotein E fragments a promising new therapeutic target for Alzheimer's disease? Vecchio FL, Bisceglia P, Imbimbo BP, Lozupone M, Latino RR, Resta E, Leone M, Solfrizzi V, Greco A, Daniele A, Watling M, Panza F, Seripa D. Ther Adv Chronic Dis 13 20406223221081605 (2022)
  7. Overview of Human HtrA Family Proteases and Their Distinctive Physiological Roles and Unique Involvement in Diseases, Especially Cancer and Pregnancy Complications. Wang Y, Nie G. Int J Mol Sci 22 10756 (2021)
  8. Interplay between HTRA1 and classical signalling pathways in organogenesis and diseases. Oka C, Saleh R, Bessho Y, Reza HM. Saudi J Biol Sci 29 1919-1927 (2022)
  9. Heterozygous Pathogenic and Likely Pathogenic Symptomatic HTRA1 Variant Carriers in Cerebral Small Vessel Disease. Xu SY, Li HJ, Li S, Ren QQ, Liang JL, Li CX. Int J Gen Med 16 1149-1162 (2023)

Articles citing this publication (40)

  1. The role of aggrecan in normal and osteoarthritic cartilage. Roughley PJ, Mort JS. J Exp Orthop 1 8 (2014)
  2. Determinants of amyloid fibril degradation by the PDZ protease HTRA1. Poepsel S, Sprengel A, Sacca B, Kaschani F, Kaiser M, Gatsogiannis C, Raunser S, Clausen T, Ehrmann M. Nat Chem Biol 11 862-869 (2015)
  3. Serine Protease HTRA1 as a Novel Target Antigen in Primary Membranous Nephropathy. Al-Rabadi LF, Caza T, Trivin-Avillach C, Rodan AR, Andeen N, Hayashi N, Williams B, Revelo MP, Clayton F, Abraham J, Lin E, Liou W, Zou CJ, Ramkumar N, Cummins T, Wilkey DW, Kawalit I, Herzog C, Storey A, Edmondson R, Sjoberg R, Yang T, Chien J, Merchant M, Arthur J, Klein J, Larsen C, Beck LH. J Am Soc Nephrol 32 1666-1681 (2021)
  4. Heterozygous mutations of HTRA1 gene in patients with familial cerebral small vessel disease. Di Donato I, Bianchi S, Gallus GN, Cerase A, Taglia I, Pescini F, Nannucci S, Battisti C, Inzitari D, Pantoni L, Zini A, Federico A, Dotti MT. CNS Neurosci Ther 23 759-765 (2017)
  5. A crayfish insulin-like-binding protein: another piece in the androgenic gland insulin-like hormone puzzle is revealed. Rosen O, Weil S, Manor R, Roth Z, Khalaila I, Sagi A. J Biol Chem 288 22289-22298 (2013)
  6. Synonymous variants in HTRA1 implicated in AMD susceptibility impair its capacity to regulate TGF-β signaling. Friedrich U, Datta S, Schubert T, Plössl K, Schneider M, Grassmann F, Fuchshofer R, Tiefenbach KJ, Längst G, Weber BH. Hum Mol Genet 24 6361-6373 (2015)
  7. Development of a therapeutic anti-HtrA1 antibody and the identification of DKK3 as a pharmacodynamic biomarker in geographic atrophy. Tom I, Pham VC, Katschke KJ, Li W, Liang WC, Gutierrez J, Ah Young A, Figueroa I, Eshghi ST, Lee CV, Kanodia J, Snipas SJ, Salvesen GS, Lai P, Honigberg L, van Lookeren Campagne M, Kirchhofer D, Baruch A, Lill JR. Proc Natl Acad Sci U S A 117 9952-9963 (2020)
  8. Age-related macular degeneration-associated silent polymorphisms in HtrA1 impair its ability to antagonize insulin-like growth factor 1. Jacobo SM, Deangelis MM, Kim IK, Kazlauskas A. Mol Cell Biol 33 1976-1990 (2013)
  9. Serum HtrA1 is differentially regulated between early-onset and late-onset preeclampsia. Teoh SS, Zhao M, Wang Y, Chen Q, Nie G. Placenta 36 990-995 (2015)
  10. Temperature-induced changes of HtrA2(Omi) protease activity and structure. Zurawa-Janicka D, Jarzab M, Polit A, Skorko-Glonek J, Lesner A, Gitlin A, Gieldon A, Ciarkowski J, Glaza P, Lubomska A, Lipinska B. Cell Stress Chaperones 18 35-51 (2013)
  11. HtrA1 activation is driven by an allosteric mechanism of inter-monomer communication. Cabrera AC, Melo E, Roth D, Topp A, Delobel F, Stucki C, Chen CY, Jakob P, Banfai B, Dunkley T, Schilling O, Huber S, Iacone R, Petrone P. Sci Rep 7 14804 (2017)
  12. Serine protease inhibitor Kazal type 1 (SPINK1) drives proliferation and anoikis resistance in a subset of ovarian cancers. Mehner C, Oberg AL, Kalli KR, Nassar A, Hockla A, Pendlebury D, Cichon MA, Goergen KM, Maurer MJ, Goode EL, Keeney GL, Jatoi A, Sahin-Tóth M, Copland JA, Radisky DC, Radisky ES. Oncotarget 6 35737-35754 (2015)
  13. Structures of insect Imp-L2 suggest an alternative strategy for regulating the bioavailability of insulin-like hormones. Roed NK, Viola CM, Kristensen O, Schluckebier G, Norrman M, Sajid W, Wade JD, Andersen AS, Kristensen C, Ganderton TR, Turkenburg JP, De Meyts P, Brzozowski AM. Nat Commun 9 3860 (2018)
  14. Whole-exome sequencing reveals a role of HTRA1 and EGFL8 in brain white matter hyperintensities. Malik R, Beaufort N, Frerich S, Gesierich B, Georgakis MK, Rannikmäe K, Ferguson AC, Haffner C, Traylor M, Ehrmann M, Sudlow CLM, Dichgans M. Brain 144 2670-2682 (2021)
  15. HTRA1 Mutations Identified in Symptomatic Carriers Have the Property of Interfering the Trimer-Dependent Activation Cascade. Uemura M, Nozaki H, Koyama A, Sakai N, Ando S, Kanazawa M, Kato T, Onodera O. Front Neurol 10 693 (2019)
  16. High-Temperature Requirement A1 (Htra1) - A Novel Regulator of Canonical Wnt Signaling. Globus O, Evron T, Caspi M, Siman-Tov R, Rosin-Arbesfeld R. Sci Rep 7 17995 (2017)
  17. Novel Function of Serine Protease HTRA1 in Inhibiting Adipogenic Differentiation of Human Mesenchymal Stem Cells via MAP Kinase-Mediated MMP Upregulation. Tiaden AN, Bahrenberg G, Mirsaidi A, Glanz S, Blüher M, Richards PJ. Stem Cells 34 1601-1614 (2016)
  18. Understanding Insulin Endocrinology in Decapod Crustacea: Molecular Modelling Characterization of an Insulin-Binding Protein and Insulin-Like Peptides in the Eastern Spiny Lobster, Sagmariasus verreauxi. Chandler JC, Gandhi NS, Mancera RL, Smith G, Elizur A, Ventura T. Int J Mol Sci 18 E1832 (2017)
  19. HTRA1-related autosomal dominant cerebral small vessel disease. Liu JY, Zhu YC, Zhou LX, Wei YP, Mao CH, Cui LY, Peng B, Yao M. Chin Med J (Engl) 134 178-184 (2020)
  20. Macrophage migration inhibitory factor (MIF) modulates trophic signaling through interaction with serine protease HTRA1. Fex Svenningsen Å, Löring S, Sørensen AL, Huynh HUB, Hjæresen S, Martin N, Moeller JB, Elkjær ML, Holmskov U, Illes Z, Andersson M, Nielsen SB, Benedikz E. Cell Mol Life Sci 74 4561-4572 (2017)
  21. Activity-modulating monoclonal antibodies to the human serine protease HtrA3 provide novel insights into regulating HtrA proteolytic activities. Singh H, Nero TL, Wang Y, Parker MW, Nie G. PLoS One 9 e108235 (2014)
  22. Molecular motion regulates the activity of the Mitochondrial Serine Protease HtrA2. Merski M, Moreira C, Abreu RM, Ramos MJ, Fernandes PA, Martins LM, Pereira PJB, Macedo-Ribeiro S. Cell Death Dis 8 e3119 (2017)
  23. ER stress-induced aggresome trafficking of HtrA1 protects against proteotoxicity. Gerhardt MJ, Marsh JA, Morrison M, Kazlauskas A, Khadka A, Rosenkranz S, DeAngelis MM, Saint-Geniez M, Jacobo SMP. J Mol Cell Biol 9 516-532 (2017)
  24. Structural basis of inactivation of human counterpart of mouse motor neuron degeneration 2 mutant in serine protease HtrA2. Wagh AR, Bose K. Biosci Rep 38 BSR20181072 (2018)
  25. Protective effects of an HTRA1 insertion-deletion variant against age-related macular degeneration in the Chinese populations. Ng TK, Liang XY, Lu F, Liu DT, Yam GH, Ma L, Tam PO, Chen H, Cen LP, Chen LJ, Yang Z, Pang CP. Lab Invest 97 43-52 (2017)
  26. Protoporphyrins enhance oligomerization and enzymatic activity of HtrA1 serine protease. Jo H, Patterson V, Stoessel S, Kuan CY, Hoh J. PLoS One 9 e115362 (2014)
  27. Role of HTRA1 in bone formation and regeneration: In vitro and in vivo evaluation. Filliat G, Mirsaidi A, Tiaden AN, Kuhn GA, Weber FE, Oka C, Richards PJ. PLoS One 12 e0181600 (2017)
  28. NBCZone: Universal three-dimensional construction of eleven amino acids near the catalytic nucleophile and base in the superfamily of (chymo)trypsin-like serine fold proteases. Denesyuk AI, Johnson MS, Salo-Ahen OMH, Uversky VN, Denessiouk K. Int J Biol Macromol 153 399-411 (2020)
  29. Purification and characterization of a novel anti-coagulant from the leech Hirudinaria manillensis. Cheng RM, Tang XP, Long AL, Mwangi J, Lai R, Sun RP, Long CB, Zhang ZQ. Zool Res 40 205-210 (2019)
  30. A distinct concerted mechanism of structural dynamism defines activity of human serine protease HtrA3. Acharya S, Dutta S, Bose K. Biochem J 477 407-429 (2020)
  31. Correlation Between Expression of High Temperature Requirement Serine Protease A1 (HtrA1) in Nucleus Pulposus and T2 Value of Magnetic Resonance Imaging. Li D, Yue J, Jiang L, Huang Y, Sun J, Wu Y. Med Sci Monit 23 1940-1946 (2017)
  32. Identification and Characterization of Plasmin-Independent Thrombolytic Enzymes. Hassan MM, Sharmin S, Kim HJ, Hong ST. Circ Res 128 386-400 (2021)
  33. Novel mutations in HTRA1-related cerebral small vessel disease and comparison with CADASIL. Zhang C, Zheng H, Li X, Li S, Li W, Wang Z, Niu S, Wang X, Zhang Z. Ann Clin Transl Neurol 9 1586-1595 (2022)
  34. Purification and Characterization of a Novel Kazal-Type Trypsin Inhibitor from the Leech of Hirudinaria manillensis. Lai Y, Li B, Liu W, Wang G, Du C, Ombati R, Lai R, Long C, Li H. Toxins (Basel) 8 E229 (2016)
  35. Structure-Based Design of a Br Halogen Bond at the Complex Interface of the Human Placental HtrA1 PDZ Domain with Its Heptapeptide Ligand. Dou SF, Liu H, Cao TM, Wen QL, Li J, Shao QC. Arch Pharm (Weinheim) 349 302-307 (2016)
  36. The crystal structure of an essential high-temperature requirement protein HtrA1 (Rv1223) from Mycobacterium tuberculosis reveals its unique features. Singh KH, Yadav S, Kumar D, Biswal BK. Acta Crystallogr D Struct Biol 74 906-921 (2018)
  37. Inhibiting HIF-1 signaling alleviates HTRA1-induced RPE senescence in retinal degeneration. Xu W, Liu X, Han W, Wu K, Zhao M, Mei T, Shang B, Wu J, Luo J, Lai Y, Yang B, Zhuo Y, Lu L, Liu Y, Tian XL, Zhao L. Cell Commun Signal 21 134 (2023)
  38. An allosteric HTRA1-calpain 2 complex with restricted activation profile. Rey J, Breiden M, Lux V, Bluemke A, Steindel M, Ripkens K, Möllers B, Bravo Rodriguez K, Boisguerin P, Volkmer R, Mieres-Perez J, Clausen T, Sanchez-Garcia E, Ehrmann M. Proc Natl Acad Sci U S A 119 e2113520119 (2022)
  39. Cryo-EM structures of inhibitory antibodies complexed with arginase 1 provide insight into mechanism of action. Palte RL, Juan V, Gomez-Llorente Y, Bailly MA, Chakravarthy K, Chen X, Cipriano D, Fayad GN, Fayadat-Dilman L, Gathiaka S, Greb H, Hall B, Handa M, Hsieh M, Kofman E, Lin H, Miller JR, Nguyen N, O'Neil J, Shaheen H, Sterner E, Strickland C, Sun A, Taremi S, Scapin G. Commun Biol 4 927 (2021)
  40. Novel Heterozygous HTRA1 Pathogenic Variant Found in a Chinese Family with Autosomal Dominant Cerebral Small Vessel Disease. Wu C, Chen L, Ke S. Ann Indian Acad Neurol 23 832-835 (2020)


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