Specific and Selective Inhibitors of Proprotein Convertases Engineered by Transferring Serpin B8 Reactive-Site and Exosite Determinants of Reactivity to the Serpin α1PDX

Biochemistry

Volumn 58, Issue 12, 2019, Pages 1679-1688

  Izaguirre, Gonzalo ^a   Arciniega, Marcelino ^b   Quezada, Andrea G ^b  

^a UNIVERSITY OF ILLINOIS AT CHICAGO   (United States)

^b INSTITUTO DE FISIOLOGÍA CELULAR   (Mexico)

Author keywords

[No Author keywords available]

Indexed keywords

BINDING SITES; MOLECULAR DYNAMICS;

CATALYTIC SITES; CONSENSUS SEQUENCE; MOLECULAR DETERMINANTS; MOLECULAR DYNAMICS SIMULATIONS; NEW APPROACHES; PROTEIN SECRETION; SELECTIVE INHIBITORS; SUBSTRATE SPECIFICITY;

MICROCOMPUTERS;

FURIN; PROPROTEIN CONVERTASE 4; PROPROTEIN CONVERTASE 5; PROPROTEIN CONVERTASE 7; PROPROTEIN CONVERTASE PACE4; SERINE PROTEINASE; SERINE PROTEINASE INHIBITOR; SERPIN B8 PROTEINASE INHIBITOR; TRANSCRIPTION FACTOR PDX 1; UNCLASSIFIED DRUG; ALPHA 1 ANTITRYPSIN; ALPHA 1-ANTITRYPSIN PORTLAND; FURIN PROTEIN, HUMAN; LIGAND;

ARTICLE; BINDING SITE; CATALYSIS; CHIMERA; CONTROLLED STUDY; ENZYME INHIBITION; ENZYME SPECIFICITY; HYDROLYSIS; MOLECULAR DYNAMICS; PRIORITY JOURNAL; PROTEIN CONFORMATION; PROTEIN DOMAIN; PROTEIN ENGINEERING; PROTEIN FUNCTION; PROTEIN SECRETION; PROTEIN TRANSPORT; REGIOSELECTIVITY; SIGNAL TRANSDUCTION; CHEMISTRY; ENZYME ACTIVE SITE; ENZYME ASSAY; GENETICS; HUMAN;

ALPHA 1-ANTITRYPSIN; CATALYTIC DOMAIN; ENZYME ASSAYS; FURIN; HUMANS; LIGANDS; MOLECULAR DYNAMICS SIMULATION; PROTEIN ENGINEERING; SERPINS; SUBSTRATE SPECIFICITY;

EID: 85063530606     PISSN: 00062960     EISSN: 15204995     Source Type: Journal    
DOI: 10.1021/acs.biochem.8b01295     Document Type: Article

References (27)

1. Seidah, N. G. and Prat, A. (2012) The biology and therapeutic targeting of the proprotein convertases. Nat. Rev. Drug Discovery 11, 367-383, 10.1038/nrd3699
2. Seidah, N. G., Mayer, G., Zaid, A., Rousselet, E., Nassoury, N., Poirier, S., Essalmani, R., and Prat, A. (2008) The activation and physiological functions of the proprotein convertases. Int. J. Biochem. Cell Biol. 40, 1111-1125, 10.1016/j.biocel.2008.01.030
3. Shiryaev, S. A., Remacle, A. G., Ratnikov, B. I., Nelson, N. A., Savinov, A. Y., Wei, G., Bottini, M., Rega, M. F., Parent, A., Desjardins, R., Fugere, M., Day, R., Sabet, M., Pellecchia, M., Liddington, R. C., Smith, J. W., Mustelin, T., Guiney, D. G., Lebl, M., and Strongin, A. Y. (2007) Targeting host cell furin proprotein convertases as a therapeutic strategy against bacterial toxins and viral pathogens. J. Biol. Chem. 282, 20847-20853, 10.1074/jbc.M703847200
4. Feliciangeli, S. F., Thomas, L., Scott, G. K., Subbian, E., Hung, C. H., Molloy, S. S., Jean, F., Shinde, U., and Thomas, G. (2006) Identification of a pH sensor in the furin propeptide that regulates enzyme activation. J. Biol. Chem. 281, 16108-16116, 10.1074/jbc.M600760200
5. Williamson, D. M., Elferich, J., Ramakrishnan, P., Thomas, G., and Shinde, U. (2013) The mechanism by which a propeptide-encoded pH sensor regulates spatiotemporal activation of furin. J. Biol. Chem. 288, 19154-19165, 10.1074/jbc.M112.442681
6. Omotuyi, I. O. (2015) Ebola virus envelope grycoprotein derived peptide in human furin-bound state: computational studies. J. Biomol. Struct. Dyn. 33, 461-470, 10.1080/07391102.2014.981207
7. Dahms, S. O., Arciniega, M., Steinmetzer, T., Huber, R., and Than, M. E. (2016) Structure of the unliganded form of the proprotein convertase furin suggests activation by a substrate-induced mechanism. Proc. Natl. Acad. Sci. U. S. A. 113, 11196-11201, 10.1073/pnas.1613630113
8. Henrich, S., Lindberg, I., Bode, W., and Than, M. E. (2005) Proprotein convertase models based on the crystal structures of furin and kexin: explanation of their specificity. J. Mol. Biol. 345, 211-227, 10.1016/j.jmb.2004.10.050
9. Remacle, A. G., Shiryaev, S. A., Oh, E. S., Cieplak, P., Srinivasan, A., Wei, G., Liddington, R. C., Ratnikov, B. I., Parent, A., Desjardins, R., Day, R., Smith, J. W., Lebl, M., and Strongin, A. Y. (2008) Substrate cleavage analysis of furin and related proprotein convertases. A comparative study. J. Biol. Chem. 283, 20897-20906, 10.1074/jbc.M803762200
10. Izaguirre, G., Qi, L., Lima, M., and Olson, S. T. (2013) Identification of serpin determinants of specificity and selectivity for furin inhibition through studies of α1PDX (α1-protease inhibitor Portland)-serpin B8 and furin active-site loop chimeras. J. Biol. Chem. 288, 21802-21814, 10.1074/jbc.M113.462804
11. Leblond, J., Laprise, M. H., Gaudreau, S., Grondin, F., Kisiel, W., and Dubois, C. M. (2006) The serpin proteinase inhibitor 8: an endogenous furin inhibitor released from human platelets. Thromb. Haemostasis 95, 243-252, 10.1160/TH05-08-0561
12. Osterwalder, T., Kuhnen, A., Leiserson, W. M., Kim, Y. S., and Keshishian, H. (2004) Drosophila serpin 4 functions as a neuroserpin-like inhibitor of subtilisin-like proprotein convertases. J. Neurosci. 24, 5482-5491, 10.1523/JNEUROSCI.5577-03.2004
13. Richer, M. J., Keays, C. A., Waterhouse, J., Minhas, J., Hashimoto, C., and Jean, F. (2004) The Spn4 gene of Drosophila encodes a potent furin-directed secretory pathway serpin. Proc. Natl. Acad. Sci. U. S. A. 101, 10560-10565, 10.1073/pnas.0401406101
14. Bentele, C., Krüger, O., Tödtmann, U., Oley, M., and Ragg, H. (2006) A proprotein convertase-inhibiting serpin with an endoplasmic reticulum targeting signal from Branchiostoma lanceolatum, a close relative of vertebrates. Biochem. J. 395, 449-456, 10.1042/BJ20051947
15. Anderson, E. D., Thomas, L., Hayflick, J. S., and Thomas, G. (1993) Inhibition of HIV-1 gp160-dependent membrane fusion by a furin-directed α1-antitrypsin variant. J. Biol. Chem. 268, 24887-24891
16. Jean, F., Stella, K., Thomas, L., Liu, G., Xiang, Y., Reason, A. J., and Thomas, G. (1998) α1-Antitrypsin Portland, a bioengineered serpin highly selective for furin: Application as an antipathogenic agent. Proc. Natl. Acad. Sci. U. S. A. 95, 7293-7298, 10.1073/pnas.95.13.7293
17. Silverman, G. A., Bird, P. I., Carrell, R. W., Church, F. C., Coughlin, P. B., Gettins, P. G., Irving, J. A., Lomas, D. A., Luke, C. J., Moyer, R. W., Pemberton, P. A., Remold-O'Donnell, E., Salvesen, G. S., Travis, J., and Whisstock, J. C. (2001) The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and a revised nomenclature. J. Biol. Chem. 276, 33293-33296, 10.1074/jbc.R100016200
18. Benjannet, S., Savaria, D., Laslop, A., Munzer, J. S., Chrétien, M., Marcinkiewicz, M., and Seidah, N. G. (1997) Alpha1-antitrypsin Portland inhibits processing of precursors mediated by proprotein convertases primarily within the constitutive secretory pathway. J. Biol. Chem. 272, 26210-26218, 10.1074/jbc.272.42.26210
19. Gettins, P. G. (2002) Serpin structure, mechanism, and function. Chem. Rev. 102, 4751-4804, 10.1021/cr010170+
20. Vidaud, D., Emmerich, J., Alhenc-Gelas, M., Yvart, J., Fiessinger, J. N., and Aiach, M. (1992) Met 358 to Arg mutation of alpha 1-antitrypsin associated with protein C deficiency in a patient with mild bleeding tendency. J. Clin. Invest. 89, 1537-1543, 10.1172/JCI115746
21. Morrison, J. F. (1969) Kinetics of the reversible inhibition of enzyme-catalyzed reactions by tight binding inhibitors. Biochim. Biophys. Acta 185, 269-286, 10.1016/0005-2744(69)90420-3
22. Scamuffa, N., Calvo, F., Chrétien, M., Seidah, N. G., and Khatib, A. M. (2006) Prorpotein convertases: lessons from knockouts. FASEB J. 20, 1954-1963, 10.1096/fj.05-5491rev
23. Seidah, N. G., Sadr, M. S., Chrétien, M., and Mbikay, M. (2013) The multifaceted proprotein convertases: their unique, redundant, complementary, and opposite functions. J. Biol. Chem. 288, 21473-21481, 10.1074/jbc.R113.481549
24. Lapierre, M., Siegfried, G., Scamuffa, N., Bontemps, Y., Calvo, F., Seidah, N. G., and Khatib, A. M. (2007) Opposing function of the proprotein convertases furin and PACE4 on breast cancer cells' malignant phenotypes: role of tissue inhibitors of metalloproteinase-1. Cancer Res. 67, 9030-9034, 10.1158/0008-5472.CAN-07-0807
25. Maret, D., Sadr, M. S., Sadr, E. S., Colman, D. R., Del Maestro, R. F., and Seidah, N. G. (2012) Opposite roles of furin and PC5A in N-cadherin processing. Neoplasia 14, 880-892, 10.1593/neo.121250
26. Komiyama, T. and Fuller, R. S. (2000) Engineered eglin c variants inhibit yeast and human proprotein processing proteases, Kex2 and furin. Biochemistry 39, 15156-15165, 10.1021/bi001907c
27. Richer, M. J., Juliano, L., Hashimoto, C., and Jean, F. (2004) Serpin mechanism of hepatitis C virus nonstructural 3 (NS3) protease inhibition: induced fit as a mechanism for narrow specificity. J. Biol. Chem. 279, 10222-10227, 10.1074/jbc.M313852200