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Proteases In Cellular Regulation Minireview Series*

T. Vanaman, R. Bradshaw
Published 1999 · Chemistry, Medicine

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Proteases form one of the largest and most diverse families of enzymes known. Once considered primarily as “enzymes of digestion,” it is now clear that proteases are involved in every aspect of organismal function. All proteases catalyze the addition of water across amide (and ester) bonds to effect cleavage using a reaction involving nucleophilic attack on the carbonyl carbon of the scissile bond. The exact mechanisms of cleavage and active site substituents vary widely among different protease subtypes. This provides the basis for the classification of proteases into the serine proteases, the cysteine proteases, the metalloproteases, etc. (see Ref. 1 for a detailed discussion of protease classification and nomenclature). More important, however, is the diversity of substrate specificity for different proteases. This involves recognizing internal peptide bonds or those of residues at the NH2 or COOH terminus of the molecule as well as side chains of the surrounding amino acids either aminoor carboxylterminal to the bond to be cleaved. It is this great diversity and potential for selectivity that provides the basis for the variety of actions of proteases in different aspects of physiological activity. The most difficult and arguably most important aspect of protease action is the control of protease activity to limit cleavage to intended substrates without general destruction of functional proteins both within and outside otherwise normal tissue. In the current miniseries, we have chosen to focus on four protease systems where major advances are being made in elucidating mechanisms of action and control in fundamental cellular processes. Not surprisingly, these are also systems with substantial linkages to disease processes. Nothing more exemplifies the need for absolute control of protease activity than the cascade of enzymes involved in the cellular death response. The first of the protease minireviews is the following contribution in this issue by Wolf and Green (2), which discusses the current state of knowledge of the caspase family of proteases and their role in apoptotic cell death. Named for the fact that they are cysteine proteases that cleave specifically at aspartic acid residues, the importance of caspases in programmed cell death was first realized in 1993 by Horvitz and co-workers (3) from the analysis of the cell death gene, ced3, in Caenorhabditis elegans. These enzymes are normally present in cells as the inactive zymogen but are activated through a very tightly regulated proteolytic cascade initiated by the cell death domain containing signaling molecules and/or sensors of the cellular metabolic state including the mitochondrion. Their activation results in degradation of essential cellular proteins and subsequently and most importantly, chromosomal DNA leading to cell death. These processes are essential for proper development even in relatively primitive animal systems. Dysfunction in caspase cascades is thought to be important in diseases ranging from cancer to neurodegenerative disorders such as Alzheimer’s disease. The second minireview in the series is a contribution by Steiner and colleagues (4), which examines the long standing but still expanding field of hormone-processing enzymes, the prohormone convertases. Indeed, the first indication of the existence of prohormones and their processing to yield biologically active products was published in 1967 by Steiner et al. (5) from pulse-chase studies of insulin production from the proinsulin precursor in islet cells. This in turn led to the discovery of a family of subtilisin-like proteases that are now known to be involved in the processing of a variety of hormone and peptide neurotransmitter precursors as well as other types of important proproteins. Relationships among this family of important enzymes and the expanding list of roles they play in physiological and pathological processes are presented in this review. The third minireview of this series by Nagase and Woessner (6) discusses the family of matrix metalloproteinases or MMPs. Like other metalloproteases, they utilize a bound metal ion, Zn, as part of their catalytic center. The MMPs act on a variety of the molecules that form the extracellular matrix including collagens, fibronectin, laminin, chondroitin sulfate proteoglycan, and others. These actions of MMPs are essential for a variety of normal biological processes where surface remodeling is required and make these enzymes important in a variety of pathologies including cancer and metastatic disease, cardiovascular diseases, and developmental and ulcerative disorders. As with other proteases, matrix metalloproteases are synthesized as inactive zymogens and are activated by proteolysis. Their activities are further controlled by a set of specific endogenous inhibitors, called TIMPs, expressed in most tissues. The coordinate regulation of matrix metalloproteinase expression and activation and TIMP expression is essential in modulating the various functions of MMPs as discussed in this review. The final contribution in this series by DeMartino and Slaughter (7) considers recent advances in our understanding of the structure, function, and regulation of the most complicated proteolytic entity known, the proteasome. This multisubunit enzyme appears to have arisen early in evolution as a large cylinder-shaped protease particle, dedicated to the compartmentalized destruction of proteins within the cell. Proteolysis is usually assisted by ATP hydrolysis, presumably due to protein unfolding, because access to the central active site cavity is restricted. Thought for many years to be composed of serine proteases, the proteasomal protease has recently been shown through detailed structural and functional analysis of the archaeon proteasome to be unique, using an NH2-terminal threonyl residue as the catalytic nucleophile (8). Additional complexes can be associated with the core proteasome adding additional regulatory properties to the complex. Most notably in eukaryotes, additional cap structures provide for the recognition of polyubiquitinated proteins as substrates. Although ubiquitination provides a handy tag to identify proteins for degradation, demonstration by Kirschner and colleagues (9) that this pathway is involved in cyclin turnover, a key step in regulating the cell cycle, first indicated that proteasomal degradation plays a direct role in cellular physiology and regulation beyond simple protein clearance. Although by no means inclusive, we hope that these reviews give our readership an appreciation for the rapid pace of developments in the field of protease research.
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