Proteases: History, Discovery, and Roles in Health and Disease

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2019 Feb 3

PMID 30710012

Citations 60

Authors

Judith S Bond

Affiliations

Soon will be listed here.

Abstract

The (JBC) has been a major vehicle for disseminating and recording the discovery and characterization of proteolytic enzymes. The pace of discovery in the protease field accelerated during the 1971-2010 period that Dr. Herb Tabor served as the JBC's editor-in-chief. When he began his tenure, the fine structure and kinetics of only a few proteases were known; now thousands of proteases have been characterized, and over 600 genes for proteases have been identified in the human genome. In this review, besides reflecting on Dr. Tabor's invaluable contributions to the JBC and the American Society for Biochemistry and Molecular Biology (ASBMB), I endeavor to provide an overview of the extensive history of protease research, highlighting a few discoveries and roles of proteases In addition, metalloproteinases, particularly meprins of the astacin family, will be discussed with regard to structural characteristics, regulation, mechanisms of action, and roles in health and disease. Proteases and protein degradation play crucial roles in living systems, and I briefly address future directions in this highly diverse and thriving research area.

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References

Ciehanover A, Hod Y, Hershko A . A heat-stable polypeptide component of an ATP-dependent proteolytic system from reticulocytes. Biochem Biophys Res Commun. 1978; 81(4):1100-5. DOI: 10.1016/0006-291x(78)91249-4. View

DeMartino G, GOLDBERG A . Identification and partial purification of an ATP-stimulated alkaline protease in rat liver. J Biol Chem. 1979; 254(10):3712-5. View

Tsukuba T, Kadowaki T, Hengst J, Bond J . Chaperone interactions of the metalloproteinase meprin A in the secretory or proteasomal-degradative pathway. Arch Biochem Biophys. 2002; 397(2):191-8. DOI: 10.1006/abbi.2001.2672. View

Dietrich J, Jiang W, Bond J . A novel meprin beta' mRNA in mouse embryonal and human colon carcinoma cells. J Biol Chem. 1996; 271(4):2271-8. DOI: 10.1074/jbc.271.4.2271. View

Sterchi E, Stocker W, Bond J . Meprins, membrane-bound and secreted astacin metalloproteinases. Mol Aspects Med. 2008; 29(5):309-28. PMC: 2650038. DOI: 10.1016/j.mam.2008.08.002. View

Bertenshaw G, Norcum M, Bond J . Structure of homo- and hetero-oligomeric meprin metalloproteases. Dimers, tetramers, and high molecular mass multimers. J Biol Chem. 2002; 278(4):2522-32. DOI: 10.1074/jbc.M208808200. View

Tsukada M, Ohsumi Y . Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 1993; 333(1-2):169-74. DOI: 10.1016/0014-5793(93)80398-e. View

De Clercq E . The design of drugs for HIV and HCV. Nat Rev Drug Discov. 2007; 6(12):1001-18. DOI: 10.1038/nrd2424. View

Garcia-Caballero A, Ishmael S, Dang Y, Gillie D, Bond J, Milgram S . Activation of the epithelial sodium channel by the metalloprotease meprin β subunit. Channels (Austin). 2010; 5(1):14-22. PMC: 3052204. DOI: 10.4161/chan.5.1.13759. View

10.

Kumar J, Bond J . Developmental expression of meprin metalloprotease subunits in ICR and C3H/He mouse kidney and intestine in the embryo, postnatally and after weaning. Biochim Biophys Acta. 2001; 1518(1-2):106-14. DOI: 10.1016/s0167-4781(01)00188-9. View

11.

Tsukuba T, Bond J . Role of the COOH-terminal domains of meprin A in folding, secretion, and activity of the metalloendopeptidase. J Biol Chem. 1998; 273(52):35260-7. DOI: 10.1074/jbc.273.52.35260. View

12.

Arolas J, Broder C, Jefferson T, Guevara T, Sterchi E, Bode W . Structural basis for the sheddase function of human meprin β metalloproteinase at the plasma membrane. Proc Natl Acad Sci U S A. 2012; 109(40):16131-6. PMC: 3479590. DOI: 10.1073/pnas.1211076109. View

13.

Lottaz D, Maurer C, Hahn D, Buchler M, Sterchi E . Nonpolarized secretion of human meprin alpha in colorectal cancer generates an increased proteolytic potential in the stroma. Cancer Res. 1999; 59(5):1127-33. View

14.

Auld D, Vallee B . Kinetics of carboxypeptidase A. II. Inhibitors of the hydrolysis of oligopeptides. Biochemistry. 1970; 9(3):602-9. DOI: 10.1021/bi00805a022. View

15.

Yura R, Bradley S, Ramesh G, Reeves W, Bond J . Meprin A metalloproteases enhance renal damage and bladder inflammation after LPS challenge. Am J Physiol Renal Physiol. 2008; 296(1):F135-44. PMC: 2636909. DOI: 10.1152/ajprenal.90524.2008. View

16.

Wolfe P, Silver P, Wickner W . The isolation of homogeneous leader peptidase from a strain of Escherichia coli which overproduces the enzyme. J Biol Chem. 1982; 257(13):7898-902. View

17.

Berlin C, Schimke R . Influence of turnover rates on the responses of enzymes to cortisone. Mol Pharmacol. 1965; 1(2):149-56. View

18.

Ciechanover A, Finley D, Varshavsky A . Ubiquitin dependence of selective protein degradation demonstrated in the mammalian cell cycle mutant ts85. Cell. 1984; 37(1):57-66. DOI: 10.1016/0092-8674(84)90300-3. View

19.

Bond J, Beynon R, Reckelhoff J, David C . Mep-1 gene controlling a kidney metalloendopeptidase is linked to the major histocompatibility complex in mice. Proc Natl Acad Sci U S A. 1984; 81(17):5542-5. PMC: 391742. DOI: 10.1073/pnas.81.17.5542. View

20.

Turk V, Stoka V, Vasiljeva O, Renko M, Sun T, Turk B . Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochim Biophys Acta. 2011; 1824(1):68-88. PMC: 7105208. DOI: 10.1016/j.bbapap.2011.10.002. View