The structural basis for neutrophil inactivation of C1̅ inhibitor

Pemberton, Philip A.; Harrison, Richard A.; Lachmann, P. J.; Carrell, Robin W.

doi:10.1042/bj2580193

Cited by 63 publications

(31 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…7). The size of this fragment is consistent with cleavage at a site near the amino terminus and at another site immediately carboxy-terminal to the P1 Arg residue (3,14,20,21). At the lowest concentration of trypsin (0.5 jug), the P2 mutant protein revealed an intermediate product, probably corresponding to a product with cleavage only at one of these two sites.…”

Section: Methodsmentioning

confidence: 53%

Unique C1 inhibitor dysfunction in a kindred without angioedema. II. Identification of an Ala443-->Val substitution and functional analysis of the recombinant mutant protein.

Zahedi¹,

Bissler²,

Davis³

et al. 1995

J. Clin. Invest.

View full text Add to dashboard Cite

We have determined the cause of an unusual Cl inhibitor abnormality in a large kindred. We previously found that half of serum Cl inhibitor molecules in affected kindred members are normal. The other half complexed with Cls but showed little complex formation with Clr. These molecules also appeared to be relatively resistant to digestion by trypsin. Taken together, the findings suggested that members of this kindred are heterozygous for an unusual Cl inhibitor mutation. Sequencing of genomic DNA from the kindred revealed that thymine has replaced cytosine in the codon for Ala443 (P2 residue) in one Cl inhibitor allele, resulting in substitution with a Val residue. To test the effect of this substitution, a mutant Cl inhibitor containing Ala"3--Val was constructed by site-directed mutagenesis and expressed in COS-1 cells. Both the Ala'3--Val mutant and the wild-type Cl inhibitor complexed completely with Cls, kallikrein, and coagulation Factor XIIa after incubation at 37°C for 60 min. In contrast, the mutant inhibitor failed to complex completely with Clr under the same conditions. Time course analysis showed that the ability of the mutant to complex with Cls is also impaired: although it complexed completely in 60 min, the rate of complex formation during a 0-60-min incubation was decreased compared with wild-type Cl inhibitor. The mutant inhibitor also formed a complex with trypsin, a serine protease that cleaves, and is not inhibited by, wild-type Cl inhibitor. The Ala"3-Val mutation therefore converts Cl inhibitor from a substrate to an inhibitor of trypsin. These studies emphasize the role of the P2 residue in the determination of target protease specificity. (J. Clin. Invest. 1995. 95:1299-1305

show abstract

Section: Methodsmentioning

confidence: 53%

Unique C1 inhibitor dysfunction in a kindred without angioedema. II. Identification of an Ala443-->Val substitution and functional analysis of the recombinant mutant protein.

Zahedi¹,

Bissler²,

Davis³

et al. 1995

J. Clin. Invest.

View full text Add to dashboard Cite

show abstract

“…Trypsin digestion of purified C1 inhibitor was as described by Aulak et al [23], and Ps.a.elastase digestion of the purified protein as described by Pemberton et al [24].…”

Section: Analysis Of the C1 Inhibitor Proteinsmentioning

confidence: 99%

Identification of a new P1 residue mutation (444Arg→Ser) in a dysfunctional C1 inhibitor protein contained in a type II hereditary angioedema plasma

1990

View full text Add to dashboard Cite

show abstract

“…C1INH, like most other serpins, reacts with target proteases (such as C1s) to form high molecular weight complexes. However, reactive center-cleaved C1INH (iC1INH) loses the ability to complex with target proteases (7,37). A number of studies have previously shown that C1INH could limit tissue injury in IR; this effect has been assumed to result from its ability to inhibit complement activation (4,13,30).…”

mentioning

confidence: 99%