C1 inhibitor hinge region mutations produce dysfunction by different mechanisms.
Heterozygosity for a mutant dysfunctional C1 inhibitor protein, a member of the serine proteinase inhibitor (serpin) superfamily, results in type II hereditary angioneurotic oedema. We identified a "hinge" region mutation in C1 inhibitor with a Val to Glu replacement at P14 Val-432. Recombinant C1 inhibitors P10 Ala-->Thr and P14Val-->Glu did not form stable complexes with fluid phase C1s or kallikrein. The P14 Val-->Glu mutant, however, was cleaved to a 96K form by C1s, while the P10 Ala-->Thr mutant was not. The recombinant P10 mutant also did not complex with C1s, kallikrein or beta-factor Xlla-Sepharose. The two mutations, therefore, result in dysfunction by different mechanisms: in one (P14 Val-->Glu), the inhibitor is converted to a substrate, while in the other (P10 Ala-->Thr), interaction with target protease is blocked.
Division of Nephrology, Children's Hospital Research Foundation, Cincinnati, Ohio.
A E
AE
Davis
K
K
Aulak
R B
RB
Parad
H P
HP
Stecklein
E
E
Eldering
C E
CE
Hack
J
J
Kramer
R C
RC
Strunk
J
J
Bissler
F S
FS
Rosen
D000409:Alanine; D000595:Amino Acid Sequence; D000799:Angioedema / Q000097:blood / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002478:Cells, Cultured; D003062:Codon / Q000235:genetics; D003174:Complement C1 Inactivator Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D003173:Complement C1s / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005971:Glutamates; D018698:Glutamic Acid; D006579:Heterozygote; D006801:Humans; D007610:Kallikreins / Q000378:metabolism; D008969:Molecular Sequence Data; D017354:Point Mutation; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013912:Threonine; D014162:Transfection; D014633:Valine
D003062:Codon; D003174:Complement C1 Inactivator Proteins; D005971:Glutamates; D011994:Recombinant Proteins; D013912:Threonine; D018698:Glutamic Acid; D007610:Kallikreins; D003173:Complement C1s; D014633:Valine; D000409:Alanine