Interactions of plasma kallikrein and C1-s with normal and dysfunctional C1(-)-inhibitor proteins from patients with hereditary angioneurotic edema: analytic gel studies

Abstract Purified preparations of normal C1(-)-inhibitor (C1(-)-INH) formed high mol wt complexes with plasma kallikrein that were stable during sodium dodecyl sulfate (SDS)-gel electrophoresis, but most of the dysfunctional C1(-)-INH proteins isolated from plasma of patients with type II hereditary angioneurotic edema (HANE) did not. Two of eight dysfunctional C1(-)-INH proteins were cleaved to lower mol wt forms that were not seen following the reaction of normal C1(-)-INH with equimolar amounts, or less, of plasma kallikrein. Only the higher mol wt component of normal C1(-)-INH (106,000 mol wt) appeared to form a stable complex with the plasma kallikrein, whereas both the 106,000 and 96,000 mol wt forms made stable complexes with C1-s. When a preparation of normal C1(-)-INH containing a homogeneous single band of C1(-)-INH was exposed to C1-s or kallikrein, a “doublet” form evolved in which the heaviest band was in the original position of native C1(-)-INH; C1- s cleavage provided a second band of 96,000; and cleavage by kallikrein, a second band of 94,000 mol wt. We conclude that dysfunctional C1(-)-INH proteins from plasma of persons with type II hereditary angioneurotic edema have impaired interactions with plasma kallikrein and are heterogeneous with respect to these interactions. Moreover, the requirements for the formation of stable complexes between normal C1(-)-INH and plasma kallikrein differed from those for stable complex formation with C1-s. The doublet form of C1(-)-INH, which purified preparations frequently demonstrate, may be due to prior cleavage by C1-s or kallikrein.

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Interactions of plasma kallikrein and C1-s with normal and dysfunctional C1(-)-inhibitor proteins from patients with hereditary angioneurotic edema: analytic gel studies

Blood ◽

10.1182/blood.v69.4.1096.bloodjournal6941096 ◽

1987 ◽

Vol 69 (4) ◽

pp. 1096-1101

Author(s):

VH Donaldson ◽

CJ Wagner ◽

B Tsuei ◽

G Kindness ◽

DH Bing ◽

...

Keyword(s):

Complex Formation ◽

Gel Electrophoresis ◽

Sodium Dodecyl ◽

Original Position ◽

Stable Complex ◽

Plasma Kallikrein ◽

Type Ii ◽

C1 Inhibitor ◽

Angioneurotic Edema ◽

Hereditary Angioneurotic Edema

Purified preparations of normal C1(-)-inhibitor (C1(-)-INH) formed high mol wt complexes with plasma kallikrein that were stable during sodium dodecyl sulfate (SDS)-gel electrophoresis, but most of the dysfunctional C1(-)-INH proteins isolated from plasma of patients with type II hereditary angioneurotic edema (HANE) did not. Two of eight dysfunctional C1(-)-INH proteins were cleaved to lower mol wt forms that were not seen following the reaction of normal C1(-)-INH with equimolar amounts, or less, of plasma kallikrein. Only the higher mol wt component of normal C1(-)-INH (106,000 mol wt) appeared to form a stable complex with the plasma kallikrein, whereas both the 106,000 and 96,000 mol wt forms made stable complexes with C1-s. When a preparation of normal C1(-)-INH containing a homogeneous single band of C1(-)-INH was exposed to C1-s or kallikrein, a “doublet” form evolved in which the heaviest band was in the original position of native C1(-)-INH; C1- s cleavage provided a second band of 96,000; and cleavage by kallikrein, a second band of 94,000 mol wt. We conclude that dysfunctional C1(-)-INH proteins from plasma of persons with type II hereditary angioneurotic edema have impaired interactions with plasma kallikrein and are heterogeneous with respect to these interactions. Moreover, the requirements for the formation of stable complexes between normal C1(-)-INH and plasma kallikrein differed from those for stable complex formation with C1-s. The doublet form of C1(-)-INH, which purified preparations frequently demonstrate, may be due to prior cleavage by C1-s or kallikrein.

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Interactions of C1(-)-inhibitors from normal persons and patients with type II hereditary angioneurotic edema with purified activated Hageman factor (factor XIIa)

Blood ◽

10.1182/blood.v75.4.911.911 ◽

1990 ◽

Vol 75 (4) ◽

pp. 911-921 ◽

Cited By ~ 3

Author(s):

VH Donaldson ◽

BH Mitchell ◽

B Everson ◽

OD Ratnoff

Keyword(s):

Polyacrylamide Gel Electrophoresis ◽

Sodium Dodecyl ◽

Type Ii ◽

C1 Inhibitor ◽

Angioneurotic Edema ◽

Hageman Factor ◽

Hereditary Angioneurotic Edema ◽

Coagulant Activity ◽

Inhibitor Type ◽

Carboxy Terminal

Abstract Activated high molecular weight Hageman factor (75 Kd) and Hageman factor carboxy-terminal fragments both formed complexes with purified C1(-)-inhibitor, but the Hageman factor fragments appeared to have a higher affinity for the C1(-)-inhibitor than activated Hageman factor. Therefore, the clot-promoting activity of activated Hageman factor might be relatively unimpaired if Hageman factor fragments are also present. Normal C1(-)-inhibitor was cleaved by Hageman factor fragments. Clot-promoting activity was not generated in Hageman factor by exposure to Hageman factor fragments, nor was Hageman factor cleaved by Hageman factor fragments. When Hageman factor was cleaved by streptokinase-activated plasminogen, a 40 Kd fragment was released. In contrast to their interactions with other proteinases, which are blocked by normal C1(-)-inhibitor, Type II C1(-)-inhibitors from plasmas of affected members of eight different kindred with this form of hereditary angioneurotic edema all inhibited the specific coagulant activity of activated Hageman factor to some degree. They did not all form complexes with activated Hageman factor that were stable during sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

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Interactions of C1(-)-inhibitors from normal persons and patients with type II hereditary angioneurotic edema with purified activated Hageman factor (factor XIIa)

Blood ◽

10.1182/blood.v75.4.911.bloodjournal754911 ◽

1990 ◽

Vol 75 (4) ◽

pp. 911-921

Author(s):

VH Donaldson ◽

BH Mitchell ◽

B Everson ◽

OD Ratnoff

Keyword(s):

Polyacrylamide Gel Electrophoresis ◽

Sodium Dodecyl ◽

Type Ii ◽

C1 Inhibitor ◽

Angioneurotic Edema ◽

Hageman Factor ◽

Hereditary Angioneurotic Edema ◽

Coagulant Activity ◽

Inhibitor Type ◽

Carboxy Terminal

Activated high molecular weight Hageman factor (75 Kd) and Hageman factor carboxy-terminal fragments both formed complexes with purified C1(-)-inhibitor, but the Hageman factor fragments appeared to have a higher affinity for the C1(-)-inhibitor than activated Hageman factor. Therefore, the clot-promoting activity of activated Hageman factor might be relatively unimpaired if Hageman factor fragments are also present. Normal C1(-)-inhibitor was cleaved by Hageman factor fragments. Clot-promoting activity was not generated in Hageman factor by exposure to Hageman factor fragments, nor was Hageman factor cleaved by Hageman factor fragments. When Hageman factor was cleaved by streptokinase-activated plasminogen, a 40 Kd fragment was released. In contrast to their interactions with other proteinases, which are blocked by normal C1(-)-inhibitor, Type II C1(-)-inhibitors from plasmas of affected members of eight different kindred with this form of hereditary angioneurotic edema all inhibited the specific coagulant activity of activated Hageman factor to some degree. They did not all form complexes with activated Hageman factor that were stable during sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

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Type II hereditary angioneurotic edema that may result from a single nucleotide change in the codon for alanine-436 in the C1 inhibitor gene.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.87.1.265 ◽

1990 ◽

Vol 87 (1) ◽

pp. 265-268 ◽

Cited By ~ 37

Author(s):

N. J. Levy ◽

N. Ramesh ◽

M. Cicardi ◽

R. A. Harrison ◽

A. E. Davis

Keyword(s):

Type Ii ◽

Nucleotide Change ◽

C1 Inhibitor ◽

Angioneurotic Edema ◽

Single Nucleotide ◽

Single Nucleotide Change ◽

Hereditary Angioneurotic Edema ◽

Inhibitor Gene

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Synthesis of C1 inhibitor in fibroblasts from patients with type I and type II hereditary angioneurotic edema.

Journal of Clinical Investigation ◽

10.1172/jci115175 ◽

1991 ◽

Vol 87 (5) ◽

pp. 1614-1620 ◽

Cited By ~ 17

Author(s):

J Kramer ◽

Y Katz ◽

F S Rosen ◽

A E Davis ◽

R C Strunk

Keyword(s):

Type I ◽

Type Ii ◽

C1 Inhibitor ◽

Angioneurotic Edema ◽

Hereditary Angioneurotic Edema

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Properties of pig synovial collagenase

Biochemical Journal ◽

10.1042/bj1890349 ◽

1980 ◽

Vol 189 (2) ◽

pp. 349-357 ◽

Cited By ~ 10

Author(s):

J A Tyler ◽

T E Cawston

Keyword(s):

Isoelectric Focusing ◽

Sodium Dodecyl Sulphate ◽

Gel Electrophoresis ◽

Specific Activity ◽

Active Form ◽

Sodium Dodecyl ◽

Type Ii ◽

Polyacrylamide Gels ◽

Optimum Ph ◽

Detectable Difference

1. Properties of a purified chemically activated form of pig synovial collagenase were examined and compared with a spontaneously active form of the enzyme. 2. The active enzyme has a specific activity of 53 000 units (microgram/min)/mg, a mol.wt. of 44 000 (by sodium dodecyl sulphate/polyarcylamide-gel electrophoresis in 2-mercaptoethanol) and pI 5.2 (by isoelectric focusing in polyacrylamide gels). 3. The activity has the characteristics of a metalloproteinase that degrades types I and III soluble or insoluble collagens in preference to type II, at an optimum pH of 6.5-8.5. 4. There is no detectable difference in these properties between the chemically activated and spontaneously active form of collagenase.

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