Mechanisms of Allergy: Important Discoveries Bergmann K-C, Ring J (eds): History of Allergy. Chem Immunol Allergy. Basel, Karger, 2014, vol 100, pp 205–213 DOI: 10.1159/000358739
The Bradykinin-Forming Cascade: A Historical Perspective Allen P. Kaplan Department of Medicine, Medical University of South Carolina, Charleston, S.C., USA
The formation of bradykinin in plasma requires interaction of three proteins, namely coagulation factor XII (Hageman factor), prekallikrein and high-molecularweight kininogen (HK). Prekallikrein and HK circulate as a bimolecular complex. Initiation of the cascade upon binding to negatively charged surfaces (or macromolecules) is dependent on factor XII autoactivation, conversion of prekallikrein to kallikrein, and a feedback activation of factor XII by kallikrein. The latter reaction is extremely rapid relative to factor XII autoactivation. The kallikrein then digests HK to liberate bradykinin. The natural surface appears to be vascular endothelial cells which express binding proteins for factor XII and HK, and activation can proceed along the cell surface. Recent findings demonstrate that prekallikrein has enzymatic activity separate from that of kallikrein such that it can stoichiometrically bind and cleave HK to liberate bradykinin. It is normally prevented from doing so by the plasma C1 inhibitor. Release of heat shock protein 90 (HSP-90) from endothelial cells can convert prekallikrein to kallikrein (stoichiometrically) within the
The plasma pathway by which bradykinin is produced is known as ‘contact activation’ because the sequence of reactions leading to bradykinin production is initiated by interaction with negatively charged surfaces. Most are familiar with this phenomenon based on drawing blood into a glass test tube so that it clots. The negative surface charge of the silicate is the ‘contact’ that starts what is known Downloaded by: UCONN Storrs 18.104.22.168 - 5/29/2015 5:23:29 PM
Factor XII The discovery of plasma deficient in factor XII (Hageman factor deficiency) by Oscar Ratnoff is a good starting point historically  and, early on, Hageman factor was known to have functions in coagulation, fibrinolysis and bradykinin formation. The enzyme kallikrein was demonstrated as an activity based on its ability to cleave a kininogen to produce bradykinin. A seminal paper by Marion Webster  was one in which she attempted to isolate those factors in serum (or activated plasma) that were required to produce bradykinin by ion exchange chromatography. A γ-globulin fraction (i.e. IgG, primarily) possessed kallikrein activity but she also defined 4 other peaks of activity which on incubation with EDTA-plasma produced bradykinin, yet did not do so when incubated with a kininogen source. These peaks therefore represented enzymatic steps that precede kininogen cleavage by kallikrein – the distinction between HK and low-molecularweight kininogen (LK) was not yet evident – their relationship to factor XII was not known, and prekallikrein was not a defined entity. My own work on the bradykinin-forming cascade began with an attempt to identify all of these peaks of activity. The result was that all 4 represented differing forms of activated factor XII; the largest is now known as factor XIIa and the smallest, and only stable form, a ‘fragment’, is factor XIIf of about 30 kDa . Fractionation of inactivated plasma revealed that incubation of the
initial γ-globulin peak obtained on ion exchange chromatography with factor XIIa or factor XIIf generated kallikrein activity and, therefore, contained a kallikrein precursor designated ‘prekallikrein’. Unactivated factor XII was purified by Cochrane and Wuepper  subsequent to the purification and characterization of the activated forms . There was controversy regarding the activation mechanism because Revak et al.  proposed that factor XIIa and factor XIIf represented two differing pathways for factor XII activation; the formation of factor XIIa required cleavage within a key disulfide bridge such that reduction yielded a heavy chain of 50 kDa and a light chain of 30 kDa, while formation of factor XIIf was a product of cleavage external to the disulfide bond. These forms of activated factor XII were renamed α-factor XIIa and β-factor XIIa , and represent terminology still used by some. However, the original mechanism  required formation of factor XIIa first (i.e. first cleavage within the disulfide bridge as an absolute requirement for an active enzyme to result) while factor XIIf represented a later cleavage product of factor XIIa. This proved to be correct once careful kinetics and bond cleavages were established . The term factor XIIa is consistent with terminology for a coagulation factor (e.g. factor XIIa, IXa, VIIa, etc.) while factor XIIf does not (it retains only 4% of the coagulant activity of factor XIIa) , yet factor XIIf activates prekallikrein readily (fig. 1) until it is inactivated by C1 inhibitor (INH). Cleavage of factor XII was shown to be a requisite for activation, which is facilitated when it is bound to negatively charged surfaces or macromolecules ; thus, the ‘contact activation’ surface renders the factor XIIa substrate. A prior idea that a conformational change occurs upon factor XII binding to surfaces that leads to active site expression was therefore disproved. Yet, incubation of purified factor XII with a synthetic substrate that turns yellow upon factor XII activation revealed seemingly spontaneous activation of factor XII (fig. 2). When the product of the reaction was examined, it was completely cleaved. The explanation turned out to be due to autoactivation  in which trace amounts of factor XIIa present in the factor XII preparation (less than 0.01%, i.e. less than 1 molecule in 10,000) is sufficient to ac-
as the intrinsic coagulation cascade with simultaneous formation of bradykinin. Three plasma proteins interact in plasma in order to produce bradykinin, namely factor XII (Hageman factor), prekallikrein and high-molecular-weight kininogen (HK). Although their interactions are quite complex, when taken together they can be considered to represent the intrinsic initiating step for blood coagulation . Thus, all three proteins interact leading to optimal conversion of factor XII to factor XIIa with bradykinin as the by-product. Conversion of factor XI to factor XIa by factor XIIa represents the second step in this coagulation cascade, but factor XI has no role in bradykinin formation.
0.4 Bradykinin 10
Bradykinin generated (μg/ml)
Fig. 1. Factor XIIf has bradykinin-forming activity and retains clotting activity. Factor XIIf was purified from plasma by ion exchange chromatography and gel electrophoresis. A concentrate of bradykinin-forming activity was subjected to SDS gel electrophoresis. The SDS gel was sliced into 32 sections; each section was sliced,
16 Slice number
solubilized and assayed for bradykinin formation as well as the ability to correct the clotting abnormality of factor XII-deficient plasma (PTT). Slices 20–26 possessed both active activities with a peak at slice 25 in a prealbumin region of the SDS gel containing two closely paced bands.
0.50 HF alone
221 μg C1 INH/ml
Fig. 2. Autoactivation of factor XII (HF) as 0.10 110.5 μg C1 INH/ml 0
count for the result. Stated another way, factor XIIa activates surface-bound factor XII to produce more factor XIIa and then factor XIIf. The reaction rate is very slow initially, then continuously increases since the concentration of enzyme is not constant (as it is
The Bradykinin-Forming Cascade
168 252 Time (min)
in usual enzymes/substrate reactions) but instead is continuously increasing. The source of this putative trace factor XIIa in plasma is unknown and is far below our abilities to measure, although some possibilities are discussed below. Tankersley and Finlay-
assessed by cleavage of Pro-Phe-Arg p-nitroanidide to liberate p-nitrophenol. OD at 250 nm is shown. A concave upward increasing curve is produced; however, a lag time of close to 1 h (60 min) is seen. Inhibition of the curvature (autoactivation) by a half normal level of C1 INH (110.5 μg/ml) and a normal C1 INH (221 μg/ml) is shown.
Fig. 3. Prekallikrein conversion of kallikrein. Reduced SDS gel electrophoresis (left gel) followed by radioautography of H3-prekallikrein (top band, 82–84 kDa) and after conversion of approximately 50% of the prekallikrein to kallikrein by incubation with factor XIIf. The heavy kallikrein chain is at the middle of the gel (50 kDa) and two light chains at 32 and 34 kDa are seen below. Further incubation with D4-DFP followed by a C14 radioautogram (right gel) reveals the incorporation of DFP into the light chains, which have the active site of kallikrein.
son  calculated that if 1 molecule each of activated factor XII and kallikrein were present in a mixture of factor XII and prekallikrein at plasma concentration, 50% of the factor XII would be activated in 13 s. That would represent a concentration of active enzyme of 5 × 10–13 M. The surface appears to create a local milieu in the contiguous fluid phase where the local concentrations of reactants are greatly increased, which increases the reaction rates of all the constituents present .
chains of 30 or 33 kDa corresponding to the two molecular forms of the starting material (fig. 3). Plasma that is congenitally deficient in prekallikrein was discovered soon thereafter  and, as anticipated, failed to generate bradykinin upon contact activation, but had a curious property regarding blood coagulation. A partial thromboplastin time performed in the standard manner was significantly prolonged; however, as the time of pre-incubation with the surface is increased prior to recalcification, the coagulation defect progressively corrects. By contrast, the abnormal PTT of factor XII-deficient plasma is unaffected. This led to the discovery that once kallikrein is produced there is a prominent feedback activation of factor XII to factor XIIa and factor XIIf [15, 16], which dramatically increases the rate of contact activation. In this fashion, factor XIIa (produced by autoactivation of factor XII) converts prekallikrein to kallikrein, and kallikrein rapidly activates factor XII. Quantitatively, the major factor XII activator is therefore kallikrein. The autocorrection of prekallikrein-deficient plasma (Fletcher factor deficiency) is due to factor XII autoactivation during the extra time of incubation with the surface, with activation of factor XI prior to recalcification. In this fashion, the need for the kallikrein feedback is bypassed. This result also confirms that factor XII activation occurs first and that kallikrein activation of factor XII is not an absolute requirement for contact activation to proceed. An alternative route by which prekallikrein might be activated in the absence of factor XII did not seem possible until recently.
Prekallikrein was purified from 4 liters of human plasma  and was demonstrated to have 2 bands on SDS gel electrophoresis that differ in carbohydrate contact, but are otherwise functionally identical, and are present in everyone. Conversion to kallikrein by factor XIIa or factor XIIf occurred by cleavage within a critical disulfide bound such that a heavy chain of 50 kDa is disulfide linked to light
The notion of two kininogens, i.e. HK and LK, appeared in the late 1960s . Their distinction was based not only on size difference, but kinetic analysis also indicated that there are kininogens (the number was actually not clear) that are readily cleaved by plasma kallikrein (with Km and Vmax consistent with that) and kininogens that are more readily cleaved by tissue kallikrein  than plasma kallikrein. Questions were then raised as to whether the lowermolecular-weight form(s) might be a cleavage prod-
the light chain (domains 5 and 6 of HK)  and domain 5 binds to initiating surfaces while domain 6 binds either prekallikrein or factor XI (but not both simultaneously; fig. 4). HK is present in sufficient molar excess such that 95% of factor XI circulated bound while, as noted above, for prekallikrein it is 75–80%. LK has no role in contact activation while tissue kallikrein does not bind to HK.
Binding to Endothelial Cells Although many substances were known to serve as initiating surfaces for contact activation (glass test tubes, glass beads, endotoxin, uric acid and pyrophosphate crystals), the nature of any ‘physiologic’ surface remained an enigma for quite some time. In 1979, a series of papers appeared indicating that HK binds to endothelial cells and platelets, and that such binding is zinc dependent . This led to a search for binding proteins on the surface of endothelial cells. One approach was to prepare an affinity column with HK, solubilize endothelial cell membranes in zinc-containing buffers, allow interaction with the HK column, elute the binding protein(s), and identify them by amino acid sequencing and/or immunologic methods. The first such protein obtained was gC1qR, a receptor for the globular heads of the first component of complement. This was first isolated and reported by Herwald et al.  and Joseph et al. . The latter authors also noted zinc-dependent binding of factor XII to gC1qR  and that factor XII and HK could compete for binding, indicating that they interacted with the same or similar binding proteins, and with comparable affinities. Thus, if either protein was bound to the cell, it could be completely displaced by a large molar excess of the other. The cell surface-binding domains of HK included domain 3 (on the C-terminal portion of the heavy chain) and domain 5 of the light chain; yet interaction with gC1qR was dependent on the light chain (i.e. domain 5), and prekallikrein could be brought to the cell surface by virtue of its binding to domain 6. In fact, a separate binding site for prekallikrein has not been found. However, a second cell surface-binding protein for HK was suspected, since a zinc-dependent binding site at domain 3 could be
uct of the higher, or the higher an aggregate of the lower. The discovery of plasma deficient in one or more kininogens was extremely helpful in sorting out the possibilities. Flaujeac-deficient plasma  possessed LK, but no HK. It was almost as abnormal as factor XII-deficient plasma, i.e. contact activation did not produce bradykinin and there were marked abnormalities of intrinsic coagulation and fibrinolysis. Williams plasma , discovered at the same time, had the same functional abnormalities but no kininogen at all. At that time we collaborated with Dr. Jack Pierce to reconstitute this plasma with HK and LK that he was able to separate by ion exchange chromatography. Each had a multiplicity of molecular forms. However, some were readily cleaved kinetically by plasma kallikrein (HK) and some were relatively resistant to cleavage (LK). When we reconstituted Williams plasma with any fraction designated HK, all abnormalities were corrected, while LK fractions had no effect. Thus, two kininogens seemed more likely than one being derived from the other, and HK appeared to have a special role in all factor XII-dependent processes. This led to further studies of the structure of HK and its interactions with prekallikrein. A key discovery was that prekallikrein and HK  circulate as a biomolecular complex (HK and factor XI also circulate as a bimolecular complex) and, at plasma equilibrium conditions, about 75–80% of prekallikrein circulates bound. Subsequent structural studies of HK demonstrated that cleavage by plasma kallikrein to release bradykinin results in the formation of kinin-free HK in which a heavy chain of 62 kDa is disulfide linked to a light chain of 56 kDa. The light chain is then further degraded to 42 kDa . Employing immunologic methods with antibodies to the heavy and light chains of HK, we could demonstrate that HK and LK shared heavy chains and that the light chains of each are completely different . Once protein sequencing as well as c-DNA and genomic cloning of HK and LK were accomplished [23–25], it became clear that they are derived by alternative splicing which begins 9 amino acids beyond the bradykinin sequence, with separate exons for their respective light chains. As anticipated, the portion of HK responsible for all the HK kinetic effects pertaining to contact activation are functions of
HK domains NH2
1 Cysteine protease inhibitor
Fig. 4. Domain structure of HK. Domains 1–3 are within the heavy chain while domains 5 and 6 are part of the light chain. Domains 2 and 3 possess cysteine protease inhibitory activity and can, for example, inactivate pain. Domain 5 contains the histidine-rich region which binds to negatively charged surfaces (as does factor XII) and domain 6 has the overlapping binding sites for prekallikrein and factor XII. Binding to endothelial cells is a function of both domains 3 and 5, which bind to cytokeratin 1 and gC1qR, respectively.
Binding to Cytokeratin 1
defined. This was first identified by Hasan et al.  to be cytokeratin 1. Since our HK affinity column led to isolation of gC1qR, we prepared an affinity column to which the heavy chain of HK was bound, and then isolated cytokeratin 1 from a solubilized endothelial cell membrane preparation. Using antisera to gC1qR and cytokeratin 1, we could demonstrate incremental inhibition of HK binding to endothelial cells. Factor XII was shown to interact with both cytokeratin 1 and gC1qR; however, the binding to gC1qR is far easier to demonstrate. These results did not explain how factor XII might competitively remove all bound HK molecules, particularly if some molecules of HK were bound to cytokeratin 1 or alternatively, if HK were simultaneously bound to cytokeratin 1 and gC1qR (i.e. a ‘two-hit binding’) with heavy chain domain 3 bound to cytokeratin 1 and light chain domain 5 bound to gC1qR. Soon thereafter, a third binding molecule, namely u-PAR (urokinase plasminogen activator recep-
6 Prekallikrein and factor XI binding
Binding to gC1qR Endothelial cell
tor), was found to bind HK. However, the affinity for cleaved, kinin-free HK was found to be much greater than that for native HK. This is consistent with the fact that we could not isolate u-PAR by affinity chromatography using HK as the ligand. However, binding of factor XII to u-PAR could be readily demonstrated. At this point, three plasma entities (HKheavy chain, HK-light chain and factor XII) could bind to 3 cell membrane proteins (gC1qR, cytokeratin 1 and u-PAR) and the possibility that all 3 cell membrane proteins might exist in a trimolecular complex was considered. It was realized that this was not the case once interactions among these proteins were studied. Joseph et al.  demonstrated that cytokeratin 1 could bind to either u-PAR or gC1qR, but u-PAR and gC1qR would not bind to each other. Then, when antisera were used to isolate the proteins from solubilized cell membranes, antibody to gC1qR led to the isolation of a complex of gC1qR and cytokeratin 1 with no u-PAR evident, while an antibody
to cytokeratin 1 led to isolation of both u-PAR and gC1qR. It became clear that these proteins exist in the cell membrane as two bimolecular complexes: gC1qR-cytokeratin 1 and u-PAR-cytokeratin 1 . The latter complex has been confirmed to be expressed along the surface of endothelial cells by immune electron microscopy . Furthermore, gC1qR is present in excess; thus, molecules of HK or factor XII could be found bound to three different cell surface binding sites, namely free gC1qR or the complexes of gC1qR-cytokeratin 1 or u-PAR-cytokeratin 1. Factor XII and HK would compete equally for gC1qR sites, while factor XII would preferentially bind to u-PAR cytokeratin 1 and HK would preferentially bind to gC1qR-cytokeratin 1. The actual distribution of HK or factor XII binding to each of these cell membrane constituents at plasma concentration of each protein is not known (fig. 5). Activation along the cell surface might localize bradykinin formation to a particular site; however, perturbation of endothelial cells to initiate activation in the manner of a ‘surface’ has not yet been demonstrated. It is of interest, however, that binding of factor XII to gC1qR can lead to slow factor XII autoactivation as is seen with more traditional initiating surfaces, while binding to cytokeratin 1 does not, and binding to u-PAR has not been tested. However,
The Bradykinin-Forming Cascade
gC1qR Cytokeratin 1
Fig. 5. Activation of the bradykinin-forming cascade along the surface of vascular endothelial cells. Zinc-dependent binding of factor XII and HK is shown and the predominant surface binding moieties are indicated.
Bradykinin B-2 receptor
incubation of endothelial cells with human plasma leads to conversion of prekallikrein to kallikrein, while plasma deficient in factor XII, prekallikrein or HK does not activate (within 1 h), indicating a requirement for all the constituents needed for contact activation. Yet further incubation for many hours leads to the activation of the factor XII-deficient plasma, but not the plasma deficient in prekallikrein or HK. When this was tested by Schmaier et al.  utilizing purified proteins bound to endothelial cells, they too found activation of prekallikrein in the absence of factor XII, presumably by some endothelial cell constituent. They questioned whether factor XII can autoactivate on endothelial cell surfaces at all. However, our own experiments, which were described above, suggest otherwise. Either way, the presence of a factor XII-independent pathway for kallikrein production was clearly evident. When the endothelial cell factor was isolated by each group, we purified heat shock protein 90 (HSP90) , which activates the complex of prekallikrein-HK in a stoichiometric reaction that requires zinc ion, while Shariat-Madar et al.  isolated a prolylcarboxypeptidase that may do the same thing. It is important to note that HSP-90, and probably prolylcarboxypeptidase, are not prekallikrein activa-
Fig. 6. Prekallikrein is incubated with an equimolar quantity of HK and a time course of bradykinin generation is shown. The HK is completely cleaved at the end of the experiment while prekallikrein reveals no conversion to kallikrein. The reaction is inhibited completely by corn trypsin inhibitor, which has no effect on plasma kallikrein.
distinction of the active site within prekallikrein from the active site of kallikrein. This reaction, in which prekallikrein cleaves HK, is normally inhibited by C1 INH (which is relevant to a discussion about hereditary angioedema). The addition of HSP-90 in a zinccontaining buffer leads to conversion of prekallikrein to kallikrein. Since HSP-90 has no known proteolytic activity, we speculate that prekallikrein can autoactivate when bound to HK plus HSP-90. It should be noted that zinc is an absolute requirement for binding of factor XII and HK to the endothelial cell surface, as well as for the interaction of HSP-90 with the prekallikrein HK complex. It is not necessary for prekallikrein cleavage of HK. Contact activation (factor XII plus prekallikrein, plus HK) has no ion requirement but the kinetics of activation are increased by the presence of zinc ion and phosphate ion, both of which are present in plasma.
A Surprise: Prekallikrein Is an Enzyme During studies of HSP-90-dependent conversion of prekallikrein, one control was to leave out the HSP90 and incubate the prekallikrein-HK complex in buffer. No conversion to kallikrein was noted, although cleavage of HK to release bradykinin was repeatedly observed (fig. 6). The formation of bradykinin was directly proportional to the addition of prekallikrein to excess HK with a maximum at a 1:1 molar ratio, indicating stoichiometric cleavage of HK . Corn trypsin inhibitor, a known inhibitor of factor XIIa and factor XIIf, inhibited HK cleavage, yet did not inhibit plasma kallikrein. This allowed the
Key questions that remain regarding the plasma bradykinin-forming pathway all have to do with issues regarding the molecular mechanisms by which the cascade is activated in vivo, and in bradykininmediated diseases in particular. Can small amounts of factor XIIa be produced in vivo by virtue of its binding to endothelial cells? Do we always have trace amounts of kallikrein present because the prekallikrein-HK complex can autoactivate in a phosphatecontaining milieu even in the presence of C1 INH? Perhaps endothelial cell activation can release HSP90 to increase the local conversion of prekallikrein to kallikrein such that kallikrein activation of factor XII becomes kinetically favored. Although factor XII autoactivation is a relatively slow process, a mixture of factor XII and prekallikrein activates rapidly even in the absence of an initiating surface. Is this due to trace amounts of each type of active enzyme present? Since this can occur in the absence of HK , one cannot invoke the enzymatic site within prekallikrein as a possible initiator, and a firm complex between factor XII and prekallikrein has never been demonstrated. These issues are of theoretical interest and the answers may be critical to understanding bradykininmediated diseases such as hereditary angioedema.
tors as factor XIIa or factor XIIf are, and require prekallikrein bound to HK as a complex. These observations do suggest the possibility of initiating the cascade by formation of kallikrein first, followed by activation of factor XII. The kinetics would then switch from stoichiometric, which is relatively inefficient for bradykinin formation, to classical Michaelis Menton kinetics, with a burst of activity that is factor XII-dependent.
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25 Takagaki Y, Kitamura N, Nakanishi S: Cloning and sequence analysis of cDNAs for human high molecular weight and low molecular weight prekininogens: primary structures of two human prekininogens. J Biol Chem 1985;260:8601–8609. 26 Thompson RE, Mandle R Jr, Kaplan AP: Studies of binding of prekallikrein and factor XI to high molecular weight kininogen and its light chain. Proc Natl Acad Sci USA 1979;76:4862–4866. 27 Schmaier AH, Kuo A, Lundberg D, et al: The expression of high molecular weight kininogen on human umbilical vein endothelial cells. J Biol Chem 1988;263:16327–16333. 28 Herwald H, Dedio J, Kellner R, et al: Isolation and characterization of the kininogenbinding protein p33 from endothelial cells: identity with the gC1q receptor. J Biol Chem 1996;271:13040–13047. 29 Joseph K, Ghebrehiwet B, Peerschke EI, et al: Identification of the zinc-dependent endothelial cell binding protein for high molecular weight kininogen and factor XII: identity with the receptor that binds to the globular ‘heads’ of C1q (gC1q-R). Proc Natl Acad Sci USA 1996;93:8552–8557. 30 Hasan AA, Zisman T, Schmaier AH: Identification of cytokeratin 1 as a binding protein and presentation receptor for kininogens on endothelial cells. Proc Natl Acad Sci USA 1998;95:3615–3620. 31 Joseph K, Tholanikunnel B, Ghebrehiwet B, et al: Interaction of high molecular weight kininogen biding proteins on endothelial cells. Thromb Haemost 2004;91:61–70. 32 Mahdi F, Shariat-Madar Z, Todd RF 3rd, et al: Expression and colocalization of cytokeratin 1 and urokinase plasminogen activator receptor on endothelial cells. Blood 2001;97:2342–2350. 33 Joseph K, Tholanikunnel B, Kaplan A: Heat shock protein 90 catalyzes activation of the prekallikrein-kininogen complex in the absence of factor XII. Proc Natl Acad Sci USA 2002;99:896–900. 34 Shariat-Madar Z, Mahdi F, Schmaier A: Identification and characterization of prolylcarboxypeptidase as an endothelial cell prekallikrein activator. J Biol Chem 2002; 277:17962–17969. 35 Joseph K, Tholanikunnel B, Kaplan A: Factor XII-independent cleavage of high molecular weight kininogen by prekallikrein and inhibition by C1 inhibitor. J Allergy Clin Immunol 2009;124:143–149.
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