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HTRA proteases: regulated proteolysis in protein quality control

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.


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.

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Figure 1: HtrA proteases regulate protein quality control pathways in the Escherichia coli cell envelope.
Figure 2: Biological functions of plant and mammalian HTRA proteases.
Figure 3: Architecture of HTRA proteases.
Figure 4: Principles of HTRA protease regulation.
Figure 5: Architecture of the HTRA PDZ domain.
Figure 6: Function of the PDZ domain in proteolysis.


  1. 1

    Page, M. J. & Di Cera, E. Evolution of peptidase diversity. J. Biol. Chem. 283, 30010–30014 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Clausen, T., Southan, C. & Ehrmann, M. The HtrA family of proteases. Implications for protein composition and cell fate. Mol. Cell 10, 443–455 (2002).

    CAS  PubMed  Google Scholar 

  3. 3

    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.

    CAS  PubMed  Google Scholar 

  4. 4

    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).

    CAS  PubMed  Google Scholar 

  5. 5

    Chien, J. et al. Serine protease HtrA1 associates with microtubules and inhibits cell migration. Mol. Cell. Biol. 29, 4177–4187 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Milner, J. M., Patel, A. & Rowan, A. D. Emerging roles of serine proteinases in tissue turnover in arthritis. Arthritis Rheum. 58, 3644–3656 (2008).

    CAS  PubMed  Google Scholar 

  7. 7

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    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.

    CAS  PubMed  Google Scholar 

  9. 9

    Coleman, H. R., Chan, C. C., Ferris, F. L. 3rd & Chew, E. Y. Age-related macular degeneration. Lancet 372, 1835–1845 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Vande Walle, L., Lamkanfi, M. & Vandenabeele, P. The mitochondrial serine protease HtrA2/Omi: an overview. Cell Death Differ. 15, 453–460 (2008).

    CAS  Google Scholar 

  11. 11

    Grau, S. et al. Implications of the serine protease HtrA1 in amyloid precursor protein processing. Proc. Natl Acad. Sci. USA 102, 6021–6026 (2005).

    CAS  PubMed  Google Scholar 

  12. 12

    García-Lorenzo, M., Sjödin, A., Jansson, S. & Funk, C. Protease gene families in Populus and Arabidopsis. BMC Plant Biol. 6, 30 (2006).

    PubMed  PubMed Central  Google Scholar 

  13. 13

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    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).

    PubMed  PubMed Central  Google Scholar 

  15. 15

    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).

    CAS  PubMed  Google Scholar 

  16. 16

    Oka, C. et al. HtrA1 serine protease inhibits signaling mediated by Tgfβ family proteins. Development 131, 1041–1053 (2004).

    CAS  PubMed  Google Scholar 

  17. 17

    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).

    CAS  PubMed  Google Scholar 

  18. 18

    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.

    CAS  PubMed  Google Scholar 

  19. 19

    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).

    CAS  PubMed  Google Scholar 

  20. 20

    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).

    CAS  PubMed  Google Scholar 

  21. 21

    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).

    CAS  PubMed  Google Scholar 

  22. 22

    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).

    CAS  PubMed  Google Scholar 

  23. 23

    Iwanczyk, J. et al. Role of the PDZ domains in Escherichia coli DegP protein. J. Bacteriol. 189, 3176–3186 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    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).

    CAS  PubMed  Google Scholar 

  26. 26

    Sun, X. et al. The thylakoid protease Deg1 is involved in photosystem-II assembly in Arabidopsis thaliana. Plant J. 62, 240–249 (2010).

    CAS  PubMed  Google Scholar 

  27. 27

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    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.

    CAS  PubMed  Google Scholar 

  29. 29

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    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).

    CAS  PubMed  Google Scholar 

  31. 31

    Ingmer, H. & Brondsted, L. Proteases in bacterial pathogenesis. Res. Microbiol. 160, 704–710 (2009).

    CAS  PubMed  Google Scholar 

  32. 32

    Baud, C. et al. Role of DegP for two-partner secretion in Bordetella. Mol. Microbiol. 74, 315–329 (2009).

    CAS  PubMed  Google Scholar 

  33. 33

    Biswas, S. & Biswas, I. Role of HtrA in surface protein expression and biofilm formation by Streptococcus mutans. Infect. Immun. 73, 6923–6934 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    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).

    CAS  PubMed  Google Scholar 

  36. 36

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Zumbrunn, J. & Trueb, B. Primary structure of a putative serine protease specific for IGF-binding proteins. FEBS Lett. 398, 187–192 (1996).

    CAS  PubMed  Google Scholar 

  39. 39

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    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).

    CAS  PubMed  Google Scholar 

  41. 41

    Launay, S. et al. HtrA1-dependent proteolysis of TGFβ controls both neuronal maturation and developmental survival. Cell Death Differ. 15, 1408–1416 (2008).

    CAS  PubMed  Google Scholar 

  42. 42

    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).

    CAS  PubMed  Google Scholar 

  43. 43

    Grau, S. et al. The role of human HtrA1 in arthritic disease. J. Biol. Chem. 281, 6124–6129 (2006).

    CAS  PubMed  Google Scholar 

  44. 44

    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).

    CAS  PubMed  Google Scholar 

  45. 45

    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).

    CAS  PubMed  Google Scholar 

  46. 46

    Winklhofer, K. F. & Haass, C. Mitochondrial dysfunction in Parkinson's disease. Biochim. Biophys. Acta 1802, 29–44 (2010).

    CAS  PubMed  Google Scholar 

  47. 47

    Fadeel, B. & Grzybowska, E. HAX-1: a multifunctional protein with emerging roles in human disease. Biochim. Biophys. Acta 1790, 1139–1148 (2009).

    CAS  PubMed  Google Scholar 

  48. 48

    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).

    CAS  PubMed  Google Scholar 

  49. 49

    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.

    CAS  PubMed  Google Scholar 

  50. 50

    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).

    CAS  PubMed  Google Scholar 

  51. 51

    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).

    CAS  PubMed  Google Scholar 

  52. 52

    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).

    CAS  PubMed  Google Scholar 

  53. 53

    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).

    CAS  PubMed  Google Scholar 

  54. 54

    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).

    CAS  PubMed  Google Scholar 

  55. 55

    Nie, G., Findlay, J. K. & Salamonsen, L. A. Identification of novel endometrial targets for contraception. Contraception 71, 272–281 (2005).

    CAS  PubMed  Google Scholar 

  56. 56

    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).

    CAS  PubMed  Google Scholar 

  57. 57

    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).

    CAS  PubMed  Google Scholar 

  58. 58

    Narkiewicz, J. et al. Expression of human HtrA1, HtrA2, HtrA3 and TGFβ1 genes in primary endometrial cancer. Oncol. Rep. 21, 1529–1537 (2009).

    CAS  PubMed  Google Scholar 

  59. 59

    Beleford, D. et al. Methylation induced gene silencing of HtrA3 in smoking-related lung cancer. Clin. Cancer Res. 16, 398–409 (2010).

    CAS  PubMed  Google Scholar 

  60. 60

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Sheng, M. & Sala, C. PDZ domains and the organization of supramolecular complexes. Annu. Rev. Neurosci. 24, 1–29 (2001).

    CAS  PubMed  Google Scholar 

  62. 62

    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.

    CAS  PubMed  Google Scholar 

  63. 63

    Li, W. et al. Structural insights into the pro-apoptotic function of mitochondrial serine protease HtrA2/Omi. Nature Struct. Biol. 9, 436–441 (2002).

    CAS  PubMed  Google Scholar 

  64. 64

    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).

    CAS  Google Scholar 

  65. 65

    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).

    CAS  PubMed  Google Scholar 

  66. 66

    Sakarya, O. et al. Evolutionary expansion and specialization of the PDZ domains. Mol. Biol. Evol. 27, 1058–1069 (2010).

    CAS  PubMed  Google Scholar 

  67. 67

    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).

    CAS  PubMed  Google Scholar 

  68. 68

    Huber, R. & Bode, W. Structural basis of the activation and action of trypsin. Acc. Chemi. Res. 11, 114–122 (1978).

    CAS  Google Scholar 

  69. 69

    Friedrich, R. et al. Staphylocoagulase is a prototype for the mechanism of cofactor-induced zymogen activation. Nature 425, 535–539 (2003).

    CAS  PubMed  Google Scholar 

  70. 70

    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.

    CAS  PubMed  Google Scholar 

  71. 71

    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).

    CAS  PubMed  Google Scholar 

  72. 72

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Fuentes-Prior, P. et al. Structural basis for the anticoagulant activity of the thrombin–thrombomodulin complex. Nature 404, 518–525 (2000).

    CAS  PubMed  Google Scholar 

  74. 74

    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).

    CAS  PubMed  Google Scholar 

  75. 75

    Hasenbein, S. et al. Conversion of a regulatory into a degradative protease. J. Mol. Biol. 397, 957–966 (2010).

    CAS  PubMed  Google Scholar 

  76. 76

    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).

    CAS  Google Scholar 

  77. 77

    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).

    CAS  Google Scholar 

  78. 78

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    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).

    CAS  PubMed  Google Scholar 

  81. 81

    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).

    CAS  PubMed  Google Scholar 

  82. 82

    Mohamedmohaideen, N. N. et al. Structure and function of the virulence-associated high-temperature requirement A of Mycobacterium tuberculosis. Biochemistry 47, 6092–6102 (2008).

    CAS  PubMed  Google Scholar 

  83. 83

    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).

    CAS  PubMed  Google Scholar 

  84. 84

    Zupkovitz, G. et al. Negative and positive regulation of gene expression by mouse histone deacetylase 1. Mol. Cell. Biol. 26, 7913–7928 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    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).

    CAS  PubMed  Google Scholar 

  86. 86

    Hauske, P. et al. Peptidic small molecule activators of the stress sensor DegS. Mol. BioSyst. 5, 980–985 (2009).

    CAS  PubMed  Google Scholar 

  87. 87

    Hauske, P. et al. Selectivity profiling of DegP substrates and inhibitors. Bioorg. Med. Chem. 17, 2920–2924 (2009).

    CAS  PubMed  Google Scholar 

  88. 88

    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).

    CAS  PubMed  Google Scholar 

  89. 89

    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).

    CAS  PubMed  Google Scholar 

  90. 90

    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).

    CAS  PubMed  Google Scholar 

  91. 91

    Groll, M., Huber, R. & Moroder, L. The persisting challenge of selective and specific proteasome inhibition. J. Pept. Sci. 15, 58–66 (2009).

    CAS  PubMed  Google Scholar 

  92. 92

    Zhang, Y. et al. Inhibition of Wnt signaling by Dishevelled PDZ peptides. Nature Chem. Biol. 5, 217–219 (2009).

    CAS  Google Scholar 

  93. 93

    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).

    CAS  PubMed  Google Scholar 

  94. 94

    Fujii, N. et al. An antagonist of dishevelled protein–protein interaction suppresses β-catenin-dependent tumor cell growth. Cancer Res. 67, 573–579 (2007).

    CAS  PubMed  Google Scholar 

  95. 95

    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).

    CAS  PubMed  Google Scholar 

  96. 96

    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).

    CAS  PubMed  Google Scholar 

  97. 97

    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).

    CAS  PubMed  Google Scholar 

  98. 98

    Kar, G., Keskin, O., Gursoy, A. & Nussinov, R. Allostery and population shift in drug discovery. Curr. Opin. Pharmacol. 10, 715–722 (2010).

    CAS  PubMed  Google Scholar 

  99. 99

    Hardy, J. A. & Wells, J. A. Searching for new allosteric sites in enzymes. Curr. Opin. Struct. Biol. 14, 706–715 (2004).

    CAS  PubMed  Google Scholar 

  100. 100

    Ganesan, R., Eigenbrot, C. & Kirchhofer, D. Structural and mechanistic insight into how antibodies inhibit serine proteases. Biochem. J. 430, 179–189 (2010).

    CAS  PubMed  Google Scholar 

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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.

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Ser protease

An enzyme that hydrolyses peptide bonds using an active site Ser residue as a nucleophile.


A cellular compartment of Gram-negative bacteria that is located between the cytoplasmic and the outer membranes.


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.

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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).

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