Chapter 5 - Regulation of Proteases by Protein Inhibitors of the Serpin Superfamily
Section snippets
Overview of the Serpin Superfamily
The serpin superfamily of protein protease inhibitors is an ancient family of proteins that are widely distributed in all the three kingdoms of life, the archea, the bacteria, and the eukaryotes, as well as in some viruses.1, 2 They represent a particularly notable advance in the evolution of proteins designed to control the activity of the proteolytic enzymes that regulate a multitude of biologic processes. Indeed, the serpins differ fundamentally from other families of protein protease
Mechanism of Action
Unlike most other protein protease inhibitors, serpins are capable of inhibiting proteases belonging to different mechanistic classes, as well as to different clades within a given class.1 While the most numerously documented examples are of serpins inhibiting serine proteases of the chymotrypsin family, there are examples of serpins inhibiting furin-like serine proteases44 and of serpins inhibiting cysteine proteases of both the cathepsin45 and caspase families.46 Furthermore, some individual
Rates of Reaction, Specificity, and Regulation
Canonical inhibitors form reversible noncovalent complexes with target proteases. The extent of inhibition is determined by the affinity of the complex and the concentration of each species. In contrast, the Michaelis complex between a serpin and protease, once formed, usually leads irreversibly to the kinetically trapped intermediate. The effectiveness of inhibition by a serpin is thus determined by the rates at which the Michaelis complex is formed and undergoes acylation, modified by the SI
Recombinant Serpins for Replacement Therapy
Normal and variant serpins have been engineered as recombinant proteins for the purposes of treating diseases whose pathogenesis is associated with dysfunctional protease regulation. As discussed earlier, serpin deficiencies can result in tissue damage and disease due to an overactivity of the proteases they regulate. One treatment for such diseases is replacement of the deficient serpin, usually with a recombinant protein to restore the natural protease/inhibitor balance.
Lung diseases that
Concluding Remarks
The serpin superfamily of protein protease inhibitors has evolved a unique conformational trapping mechanism of protease inhibition that is fundamentally different from that of the canonical lock-and-key inhibitors and that allows for novel modes of protease regulation. A common theme is the use of both RCL and exosite determinants on the serpin or on associated cofactors to lure a protease target to form an initial Michaelis encounter complex at an appropriate time and place. For serpins such
References (167)
- et al.
Serpins flex their muscle: putting the clamps on proteolysis in diverse biological systems
J Biol Chem
(2010) - et al.
Exosite determinants of serpin specificity
J Biol Chem
(2009) - et al.
A Surprising new protein superfamily containing ovalbumin, antithrombin-III, and alpha1-proteinase inhibitor
Biochem Biophys Res Commun
(1980) - et al.
α1-Antitrypsin and the serpins: variation and countervariation
Trends Biochem Sci
(1985) - et al.
Viral inhibition of inflammation: cowpox virus encodes an inhibitor of the interleukin-1beta converting enzyme
Cell
(1992) - et al.
The serpins are an expanding superfamily of structurally similar but functionally diverse proteins
J Biol Chem
(2001) - et al.
Biological activities of C1 inhibitor
Mol Immunol
(2008) - et al.
The intracellular serpin proteinase inhibitor 6 is expressed in monocytes and granulocytes and is a potent inhibitor of the azurophilic granulae protease, cathepsin G
Blood
(1999) - et al.
Crystal structure of the apoptotic suppressor CrmA in its cleaved form
Structure
(2000) - et al.
The 1.5 A crystal structure of a prokaryote serpin: controlling conformational change in a heated environment
Structure
(2003)
Endothelial cells produce a latent inhibitor of plasminogen activators that can be activated by denaturants
J Biol Chem
Formation of the antithrombin heterodimer in vivo and the onset of thrombosis
Blood
Purification and characterization of a plasminogen activator inhibitor 1 binding protein from human plasma identification as a multimeric form of S protein (vitronectin)
J Biol Chem
Serpins flex their muscle: structural insights into target peptidase recognition, polymerization and transport functions
J Biol Chem
Serpin polymerization is prevented by a hydrogen bond network that is centered on His-334 and stabilized by glycerol
J Biol Chem
A kinetic mechanism for the polymerization of alpha1-antitrypsin
J Biol Chem
Inhibition of soluble recombinant furin by human proteinase inhibitor 8
J Biol Chem
Target protease specificity of the viral serpin CrmA. Analysis of five caspases
J Biol Chem
Granzyme B is inhibited by the cowpox virus serpin cytokine response modifier A
J Biol Chem
α1-Proteinase inhibitor forms initial non-covalent and final covalent complexws with elastase analogously to other serpin-proteinase pairs, suggesting a common mechanism of inhibition
J Biol Chem
Serpin-protease complexes are trapped as stable acyl-enzyme intermediates
J Biol Chem
The pH dependence of serpin-proteinase complex dissociation reveals a mechanism of complex stabilization involving inactive and active conformational states of the proteinase which are perturbable by calcium
J Biol Chem
Canonical inhibitor-like interactions explain reactivity of α1-proteinase inhibitor Pittsburgh and antithrombin with proteinases
J Biol Chem
Active-site distortion is sufficient for proteinase inhibition by serpins
J Biol Chem
On the size of the active site in proteases. I. Papain
Biochem Biophys Res Commun
Use of NMR to study serpin function
Methods
Inactivation of thrombin by antithrombin is accompanied by inactivation of regulatory exosite 1
J Biol Chem
Serine and cysteine proteases are translocated to similar extents upon formation of covalent complexes with serpins. Fluorescence perturbation and fluorescence resonance energy transfer mapping of the protease binding site in CrmA complexes with granzyme B and caspase-1
J Biol Chem
Cytokine response modifier a inhibition of initiator caspases results in covalent complex formation and dissociation of the caspase tetramer
J Biol Chem
Plasma serine proteinase inhibitors (serpins) exhibit major conformational changes and a large increase in conformational stability upon cleavage at their reactive sites
J Biol Chem
Distribution of the native strain in human α1-antitrypsin and its association with protease inhibitor function
J Biol Chem
The serpin inhibitory mechanism is critically dependent on the length of the reactive center loop
J Biol Chem
Kinetic characterization of the protein Z-dependent protease inhibitor reaction with blood coagulation factor Xa
J Biol Chem
The F-helix of serpins plays an essential, active role in the proteinase inhibition mechanism
FEBS Lett
The importance of helix F in plasminogen activator inhibitor-1
Biochim Biophys Acta
The SEC receptor recognizes a pentapeptide neodomain of alpha 1-antitrypsin-protease complexes
J Biol Chem
Plasminogen activator inhibitor-1 contains a cryptic high affinity binding site for the low density lipoprotein receptor-related protein
J Biol Chem
Specificity of binding of the low density lipoprotein receptor-related protein (LRP) to different conformational states of the clade E serpins PAI-1 and PN-1
J Biol Chem
Cellular internalization and degradation of antithrombin III-thrombin, heparin cofactor II-thrombin, and α1-antitrypsin-trypsin complexes is mediated by the low density lipoprotein receptor-related protein
J Biol Chem
Beyond endocytosis: LRP function in cell migration, proliferation and vascular permeability
J Thromb Haemost
Kinetics of association of serine proteinases with native and oxidized α-1-proteinase inhibitor and α-1-antichymotrypsin
J Biol Chem
Mapping of the catalytic groove preferences of factor Xa reveals an inadequate selectivity for its macromolecule substrates
J Biol Chem
The contribution of the exosite residues of plasminogen activator inhibitor-1 to proteinase inhibition
J Biol Chem
Serpin structure, mechanism, and function
Chem Rev
Natural protein proteinase inhibitors and their interaction with proteinases
Eur J Biochem
Phylogeny of the serpin superfamily: implications of patterns of amino acid conservation for structure and function
Genome Res
The ovalbumin serpins revisited: perspective from the chicken genome of clade B serpin evolution in vertebrates
Proc Natl Acad Sci USA
Vertebrate serpins: construction of a conflict-free phylogeny by combining exon-intron and diagnostic site analyses
Mol Biol Evol
Antithrombin and its inherited deficiency states
Semin Hematol
Complete deficiency of plasminogen-activator inhibitor type 1 due to a frameshift mutation
N Engl J Med
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2018, Pharmacology and TherapeuticsDisruption of blood meal-responsive serpins prevents Ixodes scapularis from feeding to repletion
2018, Ticks and Tick-borne DiseasesCitation Excerpt :We are interested in understanding the role(s) of tick serine protease inhibitors (serpins) in tick feeding physiology. The tick feeding style of lacerating host tissue and sucking up blood that bleeds into the wounded area is expected to provoke host defenses such as coagulation, inflammation, complement activation, all of which are serine protease mediated pathways that are under tight control of serpins (Gettins, 2002; Huntington, 2011; Olson and Gettins, 2011). Serpin malfunctions that lead to human diseases, emphysema, thrombosis, and angioedema (Carrell and Lomas, 2002; Carrell and Travis, 1985) attest to the importance of serpins.
A novel antithrombin domain dictates the journey’s end of a proteinase
2017, Journal of Biological ChemistryCitation Excerpt :In the Michaelis complex, the proteinase is docked to the RCL of the native serpin; upon cleavage of the reactive site in the RCL, an acyl-enzyme intermediate is formed, and the N-terminal RCL fragment inserts as an extra strand into the principal β sheet of AT, rapidly translocating the attached proteinase 180° to the distal end of the serpin (Fig. 1, A and B). In this energetically favorable and stable complex, the proteinase active site is distorted, and the serpin acts as a suicide substrate (1, 2, 4, 5). Proteinase translocation, final docking, and distortion are steps in the inhibitory pathway of the branched serpin mechanism (Fig. 1C).
A structure-derived snap-trap mechanism of a multispecific serpin from the dysbiotic human oral microbiome
2017, Journal of Biological ChemistryCitation Excerpt :Serpins are comparatively large proteins of ∼350–400 residues that are grouped into peptidase inhibitor family I4 in the MEROPS database (http://merops.sanger.ac.uk)4 (28). They span over 3,000 members and also include noninhibitory variants with other functions (27, 29, 30). Serpins have been extensively studied in humans and other mammals, where they participate in inflammation, coagulation, fibrinolysis, intracellular signaling, and complement activation (29, 31).
Physiological and pathological functions of neuroserpin: Regulation of cellular responses through multiple mechanisms
2017, Seminars in Cell and Developmental Biology