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Information on EC 3.4.21.45 - complement factor I and Organism(s) Homo sapiens and UniProt Accession P05156

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EC Tree
     3 Hydrolases
         3.4 Acting on peptide bonds (peptidases)
             3.4.21 Serine endopeptidases
                3.4.21.45 complement factor I
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This record set is specific for:
Homo sapiens
UNIPROT: P05156 not found.
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Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
Inactivates complement subcomponents C3b, iC3b and C4b by proteolytic cleavage
Synonyms
complement factor i, c3b inactivator, c3bina, serine protease factor i, c3b/c4b inactivator, factor i-like activity, complement inhibitor factor i, plasma protease factor i, gcif-1, gcif-2, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C3b inactivator
-
-
-
-
C3b/C4b inactivator
-
-
C3bINA
complement C3b inactivator
-
-
-
-
complement C3b/C4b inactivator
-
-
-
-
complement C4b inactivator
-
-
-
-
complement C4bi
-
-
-
-
complement compoment C3b inactivator
-
-
-
-
complement factor I
-
-
complement inhibitor factor I
-
-
complement regulator factor I
-
-
conglutinogen-activating factor C
-
-
-
-
factor I
plasma protease factor I
-
-
serine protease Factor I
-
-
CAS REGISTRY NUMBER
COMMENTARY hide
80295-66-5
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
complement component C3 + H2O
?
show the reaction diagram
structural but not functional roles for the three N-linked oligosaccharide chains indicated, N-linked glycan pool composition of the heavy and light chains indicated
-
-
?
complement component C3b + H2O
complement component C3c + ?
show the reaction diagram
complement component C4b + H2O
complement component C4c + C4d
show the reaction diagram
benzoyl-Arg-4-methylcoumaryl-7-amide + H2O
benzoyl-Arg + 7-amino-4-methylcoumarin
show the reaction diagram
-
low activity
-
?
benzyloxycarbonyl-Gly-Gly-Arg-4-methylcoumaryl-7-amide + H2O
benzyloxycarbonyl-Gly-Gly-Arg + 7-amino-4-methylcoumarin
show the reaction diagram
-
low activity
-
?
benzyloxycarbonyl-Gly-Pro-Arg-4-methylcoumaryl-7-amide + H2O
benzyloxycarbonyl-Gly-Pro-Arg + 7-amino-4-methylcoumarin
show the reaction diagram
-
-
-
?
benzyloxycarbonyl-Leu-Leu-Arg-4-methylcoumaryl-7-amide + H2O
benzyloxycarbonyl-Leu-Leu-Arg + 7-amino-4-methylcoumarin
show the reaction diagram
-
-
-
?
benzyloxycarbonyl-Phe-Arg-4-methylcoumaryl-7-amide + H2O
benzyloxycarbonyl-Phe-Arg + 7-amino-4-methylcoumarin
show the reaction diagram
-
low activity
-
?
Boc-Asp(benzyl)-Pro-Arg-4-methylcoumarin 7-amide + H2O
?
show the reaction diagram
-
-
-
-
?
complement component C3(NH3) + H2O
?
show the reaction diagram
-
cleaved by SP domain-form
-
-
?
complement component C3b + H2O
?
show the reaction diagram
complement component C3b + H2O
complement component C3c + ?
show the reaction diagram
complement component C3b + H2O
complement component iC3b
show the reaction diagram
-
-
a major opsonin
-
?
complement component C3b + H2O
complement component iC3b + ?
show the reaction diagram
complement component C3b + H2O
inactivated C3b + ?
show the reaction diagram
complement component C3bi + H2O
?
show the reaction diagram
-
the breakdown of human erythrocyte-bound C3bi molecules in serum or plasma is mediated only by factor I
-
-
?
complement component C3bi + H2O
complement component C3c + ?
show the reaction diagram
-
complement component C3bi bound to human erythrocytes is rapidly cleaved, unlike complement component C3bi bound to other species
-
?
complement component C4b + H2O
?
show the reaction diagram
complement component C4b + H2O
complement component C4c + C4d
show the reaction diagram
complement factor C3b + H2O
?
show the reaction diagram
-
-
-
-
?
complement factor C4b + H2O
?
show the reaction diagram
-
-
-
-
?
FGR-7-amido-4-methylcoumarin + H2O
FGR + 7-amino-4-methylcoumarin
show the reaction diagram
-
-
-
-
?
methylsulfonyl-D-Phe-Gly-Arg-4-methylcoumaryl-7-amide + H2O
methylsulfonyl-D-Phe-Gly-Arg + 7-amino-4-methylcoumarin
show the reaction diagram
-
-
-
?
N-alpha-tert-butyloxycarbonyl-Val-Leu-Lys-4-methylcoumaryl-7-amide + H2O
N-alpha-tert-butyloxycarbonyl-Val-Pro-Lys + 7-amino-4-methylcoumarin
show the reaction diagram
-
low activity
-
?
N-alpha-tert-butyloxycarbonyl-Val-Pro-Arg-4-methylcoumaryl-7-amide + H2O
N-alpha-tert-butyloxycarbonyl-Val-Pro-Arg + 7-amino-4-methylcoumarin
show the reaction diagram
-
-
-
?
Phe-Gly-Arg-4-methylcoumaryl-7-amide + H2O
Phe-Gly-Arg + 7-amino-4-methylcoumarin
show the reaction diagram
-
-
-
?
Pro-Phe-Arg-4-methylcoumaryl-7-amide + H2O
Pro-Phe-Arg + 7-amino-4-methylcoumarin
show the reaction diagram
-
low activity
-
?
tert-butyloxycarbonyl-Asp(benzyl ester)-Pro-Arg-4-methylcoumaryl-7-amide + H2O
tert-butyloxycarbonyl-Asp(benzyl ester)-Pro-Arg + 7-amino-4-methylcoumarin
show the reaction diagram
-
-
-
?
tert-butyloxycarbonyl-Asp(benzyl)-Pro-Arg-7-amido-4-methylcoumarin + H2O
?
show the reaction diagram
-
-
-
-
?
tert-butyloxycarbonyl-Ile-Glu-Gly-Arg-4-methylcoumaryl-7-amide + H2O
tert-butyloxycarbonyl-Ile-Glu-Gly-Arg + 7-amino-4-methylcoumarin
show the reaction diagram
-
low activity
-
?
tert-butyloxycarbonyl-Phe-Ser-Arg-4-methylcoumaryl-7-amide + H2O
tert-butyloxycarbonyl-Phe-Ser-Arg + 7-amino-4-methylcoumarin
show the reaction diagram
-
low activity
-
?
additional information
?
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
complement component C3b + H2O
complement component C3c + ?
show the reaction diagram
complement component C4b + H2O
complement component C4c + C4d
show the reaction diagram
complement component C3(NH3) + H2O
?
show the reaction diagram
-
cleaved by SP domain-form
-
-
?
complement component C3b + H2O
?
show the reaction diagram
complement component C3b + H2O
complement component iC3b
show the reaction diagram
-
-
a major opsonin
-
?
complement component C3b + H2O
complement component iC3b + ?
show the reaction diagram
-
the complement C3 fragments C3b and iC3b appear on the surface of several virulent Staphylococcus aureus strains of capsule polysaccharide type 5 and 8. Factor I mediates the cleavage of C3b to iC3b on the surface of Staphylococcus aureus and appears to be able to function without the serum cofactor, factor H
-
?
complement component C3bi + H2O
?
show the reaction diagram
-
the breakdown of human erythrocyte-bound C3bi molecules in serum or plasma is mediated only by factor I
-
-
?
complement component C4b + H2O
?
show the reaction diagram
additional information
?
-
-
Staphylococcus aureus expressing clumping factor A (ClfA) (P336A Y338S) is more susceptible to complement-mediated phagocytosis than a ClfA-null mutant or the wild type. Unlike clumping factor A, the mutant ClfA(P336A Y338S) does not enhance factor I cleavage of C3b to iC3b and inhibits the cofactor function of factor H. Fibrinogen enhances factor I binding to clumping factor A and the Staphylococcus aureus surface
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
additional information
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Ca2+
-
two Ca2+ ions per molecule are present, each bound to one of the LDLRA domains. Crystallization data
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2-mercaptoethanol
-
10 mM, strong
4-(2-aminoethyl)benzenesulfonyl fluoride
-
0.25 mM, inhibits SP domain form and fI
amyloid beta
-
binds to complement factor I which inhibits the ability of factor I to cleave C3b to inactivated C3b. Addition of factor I restores inactivated C3b production in amyloid beta-treated RPE cells. Preincubation of factor I with amyloid beta in the presence of factor H abolishes the ability of factor I to cleave FGR-7-amino-4-methylcoumarin
-
antipain
Aprotinin
benzamidine
-
20 mM, 82% inhibition of amidolytic activity
benzenesulfonyl fluorides
-
inhibits amidolytic activity
benzyloxycarbonyl-D-Phe-Pro-methoxypropylboroglycinepinanediol ester
Cr2+
-
inhibition of proteolytic and amidolytic activity, 54% inhibition of amidolytic activity at 1 mM, 43% inhibition of proteolytic activity at 0.1 mM
Cu2+
-
23% inhibition of amidolytic activity at 1 mM
diisopropylfluorophosphate
-
-
dithiothreitol
-
1 mM, strong
epsilon-aminocaproic acid
-
20 mM, 10% inhibition of amidolytic activity
factor H
-
inhibits SP domain form
-
Fe3+
-
inhibition of proteolytic and amidolytic activity, 59% inhibition of amidolytic activity at 1 mM, 23% inhibition of proteolytic activity at 0.1 mM
Hg2+
-
26% inhibition of amidolytic activity at 1 mM
Hirudin
-
-
-
K-76COOH
-
-
leupeptin
Lima bean trypsin inhibitor
-
0.05 mM, 20% inhibition of amidolytic activity
-
NEM
-
1 mM, partial inhibition
Pefabloc TH
-
0.25 mM, 58% inhibition of amidolytic activity
Pefabloc-SC
-
0.00025 mM, complete inhibition of amidolytic activity
Pefabloc-Xa
-
0.00025 mM, 93% inhibition of amidolytic activity
PMSF
-
1 mM, 42% inhibition of amidolytic activity
Soybean trypsin inhibitor
-
0.05 mM, 37% inhibition of amidolytic activity
-
suramin
Zn2+
-
0.1 mM, 59% inhibition of proteolytic activity
additional information
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
beta1H
-
C3b receptor
-
obligate cofactor for factor I-mediated cleavage of cell bound C3bi
-
C4-binding protein
-
C4b binding protein
-
C4BP, required for activity, dependent on
-
C4bC3bINACo
-
factor H
-
JM4C8-Ag
-
purification of the pig analogue of human membrane cofactor protein, CD46/MCP, which has cofactor activity for cleavage of human and pig C3b
-
additional information
-
-
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.128
methylsulfonyl-D-Phe-Gly-Arg-4-methylcoumaryl-7-amide
-
pH 8.3, 37°C
0.027
N-alpha-tert-butyloxycarbonyl-Val-Pro-Arg-4-methylcoumaryl-7-amide
-
pH 8.3, 37°C
0.0146
tert-butyloxycarbonyl-Asp(benzyl ester)-Pro-Arg-4-methylcoumaryl-7-amide
-
pH 8.3, 37°C
0.041 - 0.203
tert-butyloxycarbonyl-Asp(benzyl)-Pro-Arg-7-amido-4-methylcoumarin
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.4
-
assay at
8.25
-
assay at
8.3
-
reaction with Phe-Gly-Arg-4-methylcoumarin-7-amide
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7 - 10
-
pH 7.0: about 45% of maximal activity, pH 10.0: about 45% of maximal activity, reaction with Phe-Gly-Arg-4-methylcoumaryl-7-amide
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
no mRNA of complement factor I detected in carcinoid cells H720, H727
Manually annotated by BRENDA team
transfected with mutant and wild-type forms of complement factor I
Manually annotated by BRENDA team
incubation of foreskin with thermolysin followed by trypsinization
Manually annotated by BRENDA team
LCC, no mRNA expression detected in LCC H661
Manually annotated by BRENDA team
AC, mRNA of complement factor I detected in H2087 and H358 but not in H1264 and A549
Manually annotated by BRENDA team
SCC, squamous cell carcinoma, mRNA of complement factor I detected in H226 but not in H157, H1385
Manually annotated by BRENDA team
SCLC, no mRNA of complement factor I detected in H69, H82, H187, H209, H345, N417, H510
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
surface-bound form of the serine protease domain
Manually annotated by BRENDA team
-
upon EndoH digestion, a large fraction of wild-type complement factor I is EndoH sensitive and displays faster mobility upon electrophoresis representing protein in endoplasmic reticulum still undergoing processing, but significant amount of wild-type complement factor I is resistant to EndoH indicates transport to late secretory compartments and beyond
Manually annotated by BRENDA team
-
upon EndoH digestion, a large fraction of wild-type complement factor I is EndoH sensitive and displays faster mobility upon electrophoresis representing protein in endoplasmic reticulum still undergoing processing, but significant amount of wild-type complement factor I is resistant to EndoH indicates transport to late secretory compartments and beyond
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
physiological function
additional information
-
the enzyme can be selectively bound by Prevotella intermedia ATCC 25611 cells, the bound enzyme retains its serine protease activity, interaction analysis, overview
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
CFAI_HUMAN
583
0
65750
Swiss-Prot
Secretory Pathway (Reliability: 1)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
1622
A2G2, deduced molecular weight of N-linked glycan structure
1824
A3G2, deduced molecular weight of N-linked glycan structure
1912
A2G2S1, deduced molecular weight of N-linked glycan structure
2115
A3G2S1, deduced molecular weight of N-linked glycan structure
2202
A2G2S2, deduced molecular weight of N-linked glycan structure
2277
A3G3S1, deduced molecular weight of N-linked glycan structure
2405
A3G2S2, deduced molecular weight of N-linked glycan structure
2567
A3G3S2, deduced molecular weight of N-linked glycan structure
27590
calculated for non-glycosylated light chain, estimated basing upon results of the N-linked glycan analysis
30270
estimated for light chain of a partially deglycosylated factor I bearing a single N-linked Man3GlcNAc2 core structure at each glycosylation site
35290
calculated for non-glycosylated heavy chain, estimated basing upon results of the N-linked glycan analysis
3569
approximate reduction of molecular weight for the heavy chain after partial deglycosylation of native protein with ABS, BTG and GuH exoglycosidases
35900
native light chain, estimated basing upon results from the N-linked glycan analysis
37000
light chain of
37960
estimated for heavy chain of a partially deglycosylated factor I bearing a single N-linked Man3GlcNAc2 core structure at each glycosylation site
38000
light chain of
41530
native heavy chain, estimated basing upon results from the N-linked glycan analysis
50000
5632
approximate reduction of molecular weight for the light chain after partial deglycosylation of native protein with ABS, BTG and GuH exoglycosidases
62880
total calculated molecular weight for non-glycosylated factor I, estimated basing upon results of the N-linked glycan analysis
68230
estimated for total protein bearing a single N-linked Man3GlcNAc2 core structure at each glycosylation site
77430
deduced for total protein of the native factor I basing upon results from the N-linked glycan analysis
88000
892
Man3GlcNAc2 core, deduced molecular weight of N-linked glycan structure
90000
unprocessed, under reducing conditions, SDS-PAGE
9201
approximate reduction of molecular weight for total molecule of factor I after partial deglycosylation of native protein with ABS, BTG and GuH exoglycosidases
38000
50000
58000
-
SDS-PAGE
66000
-
nonglycosylated proenzyme
75000
-
x * 75000, SDS-PAGE
88000
90000
-
Western blotting, unprocessed CFI protein under reducing conditions
additional information
mutant protein reveals a slightly different migration pattern during electrophoresis under reducing conditions, due to proximity of the mutation to a cysteine residue
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
heterodimer
dimer
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
glycoprotein
side-chain modification
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
to 2.7 A resolution. The shape of factor I is bilobal, with the heavy and light chains making up the two halves of a brick. The arrangement of the domains in the larger heavy-chain lobe forms a ring structure, with the N-terminal FIMAC domain contacting the C-terminal LDLRA domains. This contact is linked covalently by a disulfide bridge between Cys15 and Cys237. Mapping of disease-associated gene polymorphisms and mutations known to alter cofactor-assisted C3b/C4b cleavage by factor I onto the factor I structure implies allosteric regulation of light-chain activity by contact of the heavy chain. Modeling of the ternary complex of factor I, factor H, and C3b
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
D501N
amino acid exchange in the serine protease domain, resulting in secreted proteins that lack cofactor function of complement components C3b and C4b
D506V
amino acid exchange in the serine protease domain, resulting in secreted proteins that lack cofactor function of complement components C3b and C4b
G243D
cofactor function of complement components C3b and Cb4 not affected
G261D
mutation in the complement factor I heavy chain associated with atypical hemolytic uremic syndrome, recombinant protein generated, activity tested
I322T
amino acid exchange in the serine protease domain, resulting in secreted proteins that lack cofactor function of complement components C3b and C4b
M120I
R299W
amino acid exchange in the heavy chain, about 30% activity retained
R388H
cofactor function of complement components C3b and Cb4 not affected
A222G
-
secretion of mutant protein significantly lower compared to wild-type when expressed in human embryonic kidney cells. Mutant cleaves the alpha'-chains of complement factor C4b and C3b as efficiently as wild-type in solution. Compared to wild-type mutant A22G shows impaired cleavage of complement factor C3b on the surface of sheep erythrocytes. Mutant cleaves C3b alpha'chain on the surface of endothelial cells (HUVEV-cells) as efficiently as wild-type
C196S
-
naturally occuring mutation, causes a failure in secretion of the enzyme
C237Y
-
mutation affects secretion, is expressed in smaller amounts as the wild-type. Does not degrade C4b and C3b as efficiently as the wild-type
C25F
-
mutant is as efficiently expressed in human embryonic kidney cells as wild-type, mutant protein is not secreted. Mutant is sensitive to EndoH digestion, indicating that it does not reach the late Golgi compartment and is retained in the endoplasmic reticulum
D104S
-
site-directed mutagenesis, altered kinetics compared to the wild-type
D207N/Q219A
-
Km (tert-butyloxycarbonyl-Asp(benzyl)-Pro-Arg-7-amido-4-methylcoumarin) and Vmax similar to wild-type
D207N/Q219A/M220A/K221Q
-
Km (tert-butyloxycarbonyl-Asp(benzyl)-Pro-Arg-7-amido-4-methylcoumarin) and Vmax similar to wild-type
D26N/K27Q/F29A/Q31A
-
Km (tert-butyloxycarbonyl-Asp(benzyl)-Pro-Arg-7-amido-4-methylcoumarin) similar to wild-type, Vmax significantly increased compared to wild-type. Compared to wild-type mutant shows strongly impaired activity in degradation of fluid-phase complement factor C4b or C3b and in the degradation of surface-bound C3b deposited on sheep erythrocytes
D385N/K387S
-
site-directed mutagenesis, altered kinetics compared to the wild-type
D420N/N422T
-
site-directed mutagenesis, the mutation in the serine protease domain decreases the binding of the enzyme to substrate analogue C3met
D497N
-
site-directed mutagenesis, altered kinetics compared to the wild-type
D501N
-
mutant is as efficiently expressed and secreted in human embryonic kidney cells as wild-type, mutant does not degrade complement factor C4b or C3b. In contrast to wild-type mutant D501N does not cleave C3b alpha'chain on the surface of endothelial cells (HUVEV-cells)
D506V
-
leads to partial IF-deficiency
F29A/Q31A
-
Km (tert-butyloxycarbonyl-Asp(benzyl)-Pro-Arg-7-amido-4-methylcoumarin) similar to wild-type, Vmax significantly increased compared to wild-type. Compared to wild-type mutant shows strongly impaired activity in degradation of fluid-phase complement factor C4b or C3b
F82N/N84T
-
site-directed mutagenesis, the mutation in the FIMAC domain impairs enzyme activity, which is rescued by deglycosylation of the mutant
F94A/K182Q/R184Q
-
Km (tert-butyloxycarbonyl-Asp(benzyl)-Pro-Arg-7-amido-4-methylcoumarin) similar to wild-type, Vmax significantly increased compared to wild-type. Compared to wild-type mutant shows strongly impaired activity in degradation of fluid-phase complement factor C4b or C3b. Mutant shows greatly impaired activity in the degradation of surface-bound C3b deposited on sheep erythrocytes
G170V
-
is expressed at low levels. Does degrade C4b and C3b
G71V
-
naturally occuring mutation, causes a failure in secretion of the enzyme
H165R
-
mutant is as efficiently expressed and secreted in human embryonic kidney cells as wild-type. Mutant cleaves the alpha'-chains of complement factor C4b and C3b more efficiently than wild-type in the presence of C4b-binding protein and factor H as cofactors in solution. Cleavage of complement factor C3b on the surface of sheep erythrocytes is similar to wild-type. In the presence of membrane cofactor protein mutant cleaves C3b alpha'chain on the surface of endothelial cells (HUVEV-cells) more efficiently than wild-type
H400L
-
mutation affects secretion, is expressed at low levels. Does degrade C4b and C3b
I339M
-
mutation affects secretion, is expressed at low levels
K124N
-
site-directed mutagenesis, altered kinetics compared to the wild-type
K124Q/R150Q/F151A/K152Q
-
Km (tert-butyloxycarbonyl-Asp(benzyl)-Pro-Arg-7-amido-4-methylcoumarin) and Vmax similar to wild-type
K182N/R184S
-
site-directed mutagenesis, altered kinetics compared to the wild-type
K182Q/R184Q
-
Km (tert-butyloxycarbonyl-Asp(benzyl)-Pro-Arg-7-amido-4-methylcoumarin) and Vmax similar to wild-type. Mutant shows similar activity to wild-type in degradation of fluid-phase complement factor C4b or C3b and in the degradation of surface-bound C3b deposited on sheep erythrocytes
K326N/A328T
-
site-directed mutagenesis, the mutation in the serine protease domain decreases the binding of the enzyme to substrate analogue C3met
K458N/N460T
-
site-directed mutagenesis, altered kinetics compared to the wild-type
K51A/R62A
-
Km (tert-butyloxycarbonyl-Asp(benzyl)-Pro-Arg-7-amido-4-methylcoumarin) and Vmax similar to wild-type, only mutant in the FI and membrane attack complex domain (FIMAC) which shows some activity in degradation of fluid-phase complement factor C4b or C3b
K51A/R62A/L73A/L76A/F82A
-
Km (tert-butyloxycarbonyl-Asp(benzyl)-Pro-Arg-7-amido-4-methylcoumarin) and Vmax similar to wild-type
K93Q/F94A
-
Km (tert-butyloxycarbonyl-Asp(benzyl)-Pro-Arg-7-amido-4-methylcoumarin) and Vmax similar to wild-type. Compared to wild-type mutant shows decreased but not abolished activity in degradation of fluid-phase complement factor C4b or C3b. Mutant shows impaired activity in the degradation of surface-bound C3b deposited on sheep erythrocytes
L171N
-
site-directed mutagenesis, altered kinetics compared to the wild-type
L289x
-
deletion mutant (c.893delC) leading to a premature stop codon. Mutant protein is not secreted when expressed in human embryonic kidney cells
L73A/L76A/F82A
-
Km (tert-butyloxycarbonyl-Asp(benzyl)-Pro-Arg-7-amido-4-methylcoumarin) and Vmax similar to wild-type
M120V
-
mutant is as efficiently expressed in human embryonic kidney cells as wild-type, secretion is significantly lower compared to wild-type. Mutant cleaves the alpha'-chains of complement factor C4b and C3b more efficiently than wild-type in the presence of C4b-binding protein and factor H as cofactors in solution. Mutant cleaves complement factor C3b more efficiently in the presence of membrane cofactor protein in solution. Compared to wild-type mutant M120V shows enhanced cleavage of complement factor C3b on the surface of sheep erythrocytes. In the presence of membrane cofactor protein mutant cleaves C3b alpha'chain on the surface of endothelial cells (HUVEV-cells) more efficiently than wild-type
M220A/K221Q
-
Km (tert-butyloxycarbonyl-Asp(benzyl)-Pro-Arg-7-amido-4-methylcoumarin) and Vmax similar to wild-type
N133S
-
mutant protein is not secreted when expressed in human embryonic kidney cells, mutant is sensitive to EndoH digestion, indicating that it does not reach the late Golgi compartment and is retained in the endoplasmic reticulum
N404T
-
site-directed mutagenesis, the mutation in the serine protease domain decreases the binding of the enzyme to substrate analogues C3met and C4met
P32A
-
mutant is as efficiently expressed and secreted in human embryonic kidney cells as wild-type. P32A mutant shows impaired function towards degradation of the alpha'-chains of complement factor C4b at the two highest concentrations and of the alpha'-chain of C3b at the highest concentration when factor H is used as cofactor. No significant impairment when complement receptor 1 and membrane cofactor protein 1 are used as cofactors. Compared to wild-type mutant P32A shows impaired cleavage of complement factor C3b on the surface of sheep erythrocytes. Mutant cleaves C3b alpha'chain on the surface of endothelial cells (HUVEV-cells) as efficiently as wild-type
Q210N/V212T
-
site-directed mutagenesis, altered kinetics compared to the wild-type
Q219N/K221S
-
site-directed mutagenesis, altered kinetics compared to the wild-type
Q232K
-
mutation affects secretion, is expressed in smaller amounts as the wild-type. Does degrade C4b and C3b
Q242N/K244S
-
site-directed mutagenesis, the mutation in the LDLr2 domain decreases the binding of the enzyme to substrate analogues C3met and C4met
Q257N/Q259S
-
site-directed mutagenesis, the mutation in the LDLr2 domain decreases the binding of the enzyme to substrate analogues C3met and C4met
Q336x
-
truncated mutant can be expressed, in vitro, at a level similar to that of the wild-type, but is not functional because it lacks the serine protease domain. Is not detected in serum of the patient
R130Q/R169Q
-
Km (tert-butyloxycarbonyl-Asp(benzyl)-Pro-Arg-7-amido-4-methylcoumarin) and Vmax similar to wild-type
R150Q/F151A/K152Q
-
Km (tert-butyloxycarbonyl-Asp(benzyl)-Pro-Arg-7-amido-4-methylcoumarin) and Vmax similar to wild-type
R201S
-
present only in Far East populations with frequencies of about 0.03 in the main island of Japan and lower than 0.01 in Okinawa and Korea
R299W
-
mutant is as efficiently expressed in human embryonic kidney cells as wild-type, secretion is significantly lower compared to wild-type. Mutant cleaves the alpha'-chains of complement factor C4b and C3b as efficiently as wild-type in solution. Cleavage of complement factor C3b on the surface of sheep erythrocytes is similar to wild-type. In the presence of membrane cofactor protein mutant cleaves C3b alpha'chain on the surface of endothelial cells (HUVEV-cells) more efficiently than wild-type
R35N/I37T
-
site-directed mutagenesis, the mutation in the FIMAC domain impairs enzyme activity, which is rescued by deglycosylation of the mutant
R365N
-
site-directed mutagenesis, the mutation in the serine protease domain decreases the binding of the enzyme to substrate analogues C3met and C4met
R406H
-
present almost exclusively in East Asians and at highest frequencies in southern Chinese Han and Thais
R456x
-
point mutant leading to a premature stop codon. Mutant protein is not secreted when expressed in human embryonic kidney cells
R502L
-
must have arisen in a southeastern part of Asia and thereafter has spread to neighboring populations
R61N
-
site-directed mutagenesis, altered kinetics compared to the wild-type
S250L
-
mutation affects secretion, is expressed in smaller amounts as the wild-type. Cleaves C4b and C3b in the same manner as the wild-type
S561N/Y563T
-
site-directed mutagenesis, the mutation in the serine protease domain impairs enzyme activity, which is rescued by deglycosylation of the mutant
T520x
-
insertion mutant (c. 1610insAT) leading to a premature stop codon, mutant protein is not secreted when expressed in human embryonic kidney cells
T54N/V56T
-
site-directed mutagenesis, altered kinetics compared to the wild-type
V212A/L236A
-
Km (tert-butyloxycarbonyl-Asp(benzyl)-Pro-Arg-7-amido-4-methylcoumarin) similar to wild-type, Vmax significantly increased compared to wild-type. Compared to wild-type mutant shows strongly impaired activity in degradation of fluid-phase complement factor C4b or C3b. Mutant shows no activity in the degradation of surface-bound C3b deposited on sheep erythrocytes
V252A/I267A
-
Km (tert-butyloxycarbonyl-Asp(benzyl)-Pro-Arg-7-amido-4-methylcoumarin) similar to wild-type, Vmax significantly increased compared to wild-type. Compared to wild-type mutant shows strongly impaired activity in degradation of fluid-phase complement factor C4b or C3b. Mutant shows no activity in the degradation of surface-bound C3b deposited on sheep erythrocytes
W127X
W468x
-
deletion mutant (c.1446-1450 delTTCAC) leading to a premature stop codon, mutant is as efficiently expressed in human embryonic kidney cells as wild-type but protein is not secreted
W528x
-
point mutant leading to a premature stop codon. Mutant protein is not secreted when expressed in human embryonic kidney cells
Y369S
-
patient heterozygous for a novel missense mutation in CFI. This polymorphism is within a functional domain. It is located in the 38 kDa chain of the protein within the serine protease domain that is linked by a disulfide bond to the noncatalytic heavy chain of factor I
additional information
pH STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
2.2
-
stable
95489
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
56
-
30 min, stable
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
stable to 0.15 M hydrazine or 2 M guanidine-HCl
-
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
4°C, neutral pH, stable for several weeks
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
gel filtration
gel filtration, recombinant protein
gel filtration, SDS-PAGE
recombinant and native proteins, gel filtration, SDS-PAGE
by size-exclusion chromatography
-
extracellular enzyme from serum
-
generation of intact form of SP domain, purifiaction by affinity chromatography on MRC-OX21-Sepharose
-
on Ni-NTA resin
-
using Ni-NTA chromatography
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli, mutant and unmodified proteins
serine protease region of factor I flanked by the Xho I site and cloned into vector pCXN2L/FLAG-PI. Plasmid transformed into Escherichia coli C600 and amplified. Expression in CHO cells
cloned into the eukaryotic expression vector pcDNA3 with addition of an N-terminal His-tag and transiently expressed in human embryonic kidney 293 cells
-
expressed as an N-terminal His-tagged fusion protein in human embryonic kidney cells
-
expression of His6-tagged wild-type and mutant enzymes in HEK-293 cells
-
HEK-293 cells transiently transfected with wild-type CFI or recombinant mutant constructs
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
medicine
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Ekdahl, K.N.; Nilsson, U.R.; Nilsson, B.
Inhibition of factor I by diisopropylfluorophosphate. Evidence of conformational changes in factor I induced by C3b and additional studies on the specificity of factor I
J. Immunol.
144
4269-4274
1990
Homo sapiens
Manually annotated by BRENDA team
Medicus, R.G.; Melamed, J.; Arnaout, M.A.
Role of human factor I and C3b receptor in the cleavage of surface-bound C3bi molecules
Eur. J. Immunol.
13
465-470
1983
Homo sapiens
Manually annotated by BRENDA team
Hsiung, L.; Barclay, A.N.; Brandon, M.R.; Sim, E.; Porter, R.R.
Purification of human C3b inactivator by monoclonal-antibody affinity chromatography
Biochem. J.
203
293-298
1982
Homo sapiens
Manually annotated by BRENDA team
Crossley, L.G.
C3b inactivator and beta1H
Methods Enzymol.
80
112-124
1981
Homo sapiens
Manually annotated by BRENDA team
Nagasawa, S.; Ichihara, C.; Stroud, R.M.
Cleavage of C4b by C3b inactivator: production of a nicked form of C4b, C4b', as an intermediate cleavage product of C4b by C3b inactivator
J. Immunol.
125
578-582
1980
Homo sapiens
Manually annotated by BRENDA team
Fujita, T.; Nussenzweig, V.
The role of C4-binding protein and beta1H in proteolysis of C4b and C3b
J. Exp. Med.
150
267-276
1979
Homo sapiens
Manually annotated by BRENDA team
Gaither, T.A.; Hammer, C.H.; Frank, M.M.
Studies of the molecular mechanisms of C3b inactivation and a simplified assay of beta1H and the C3b inactivator (C3bINA)
J. Immunol.
123
1195-1204
1979
Homo sapiens
Manually annotated by BRENDA team
DiScipio, R.G.
The fractionation of human plasma proteins
Protein Expr. Purif.
5
178-186
1994
Homo sapiens
Manually annotated by BRENDA team
Van den Berg, C.W.; Perez de la Lastra, J.M.; Llanes, D.; Morgan, B.P.
Purification and characterization of the pig analogue of human membrane cofactor protein (CD46/MCP)
J. Immunol.
158
1703-1709
1997
Homo sapiens, Sus scrofa
Manually annotated by BRENDA team
Ekdahl, K.N.; Nilsson, B.
Phosphorylation of complement component C3 and C3 fragments by a human platelet protein kinase
J. Immunol.
154
6402-6510
1995
Homo sapiens
-
Manually annotated by BRENDA team
Cunnion, K.M.; Hair, P.S.; Buescher, E.S.
Cleavage of complement C3b to iC3b on the surface of Staphylococcus aureus is mediated by serum complement factor I
Infect. Immun.
72
2858-2863
2004
Homo sapiens
Manually annotated by BRENDA team
Tsiftsoglou, S.A.; Sim, R.B.
Human complement factor I does not require cofactors for cleavage of synthetic substrates
J. Immunol.
173
367-375
2004
Homo sapiens
Manually annotated by BRENDA team
Tsiftsoglou, S.A.; Willis, A.C.; Li, P.; Chen, X.; Mitchell, D.A.; Rao, Z.; Sim, R.B.
The catalytically active serine protease domain of human complement factor I
Biochemistry
44
6239-6249
2005
Homo sapiens
Manually annotated by BRENDA team
Kavanagh, D.; Kemp, E.J.; Mayland, E.; Winney, R.J.; Duffield, J.S.; Warwick, G.; Richards, A.; Ward, R.; Goodship, J.A.; Goodship, T.H.
Mutations in complement factor I predispose to development of atypical hemolytic uremic syndrome
J. Am. Soc. Nephrol.
16
2150-2155
2005
Homo sapiens
Manually annotated by BRENDA team
Cunnion, K.M.; Buescher, E.S.; Hair, P.S.
Serum complement factor I decreases Staphylococcus aureus phagocytosis
J. Lab. Clin. Med.
146
279-286
2005
Homo sapiens
Manually annotated by BRENDA team
Tsiftsoglou, S.A.; Arnold, J.N.; Roversi, P.; Crispin, M.D.; Radcliffe, C.; Lea, S.M.; Dwek, R.A.; Rudd, P.M.; Sim, R.B.
Human complement factor I glycosylation: structural and functional characterisation of the N-linked oligosaccharides
Biochim. Biophys. Acta
1764
1757-1766
2006
Homo sapiens (P05156), Homo sapiens
Manually annotated by BRENDA team
Nilsson, S.C.; Karpman, D.; Vaziri-Sani, F.; Kristoffersson, A.C.; Salomon, R.; Provot, F.; Fremeaux-Bacchi, V.; Trouw, L.A.; Blom, A.M.
A mutation in factor I that is associated with atypical hemolytic uremic syndrome does not affect the function of factor I in complement regulation
Mol. Immunol.
44
1835-1844
2007
Homo sapiens (P05156)
Manually annotated by BRENDA team
Timar, K.K.; Junnikkala, S.; Dallos, A.; Jarva, H.; Bhuiyan, Z.A.; Meri, S.; Bos, J.D.; Asghar, S.S.
Human keratinocytes produce the complement inhibitor factor I: Synthesis is regulated by interferon-gamma
Mol. Immunol.
44
2943-2949
2007
Homo sapiens (P05156), Homo sapiens
Manually annotated by BRENDA team
Okroj, M.; Hsu, Y.F.; Ajona, D.; Pio, R.; Blom, A.M.
Non-small cell lung cancer cells produce a functional set of complement factor I and its soluble cofactors
Mol. Immunol.
45
169-179
2008
Homo sapiens (P05156)
Manually annotated by BRENDA team
Kavanagh, D.; Richards, A.; Noris, M.; Hauhart, R.; Liszewski, M.K.; Karpman, D.; Goodship, J.A.; Fremeaux-Bacchi, V.; Remuzzi, G.; Goodship, T.H.; Atkinson, J.P.
Characterization of mutations in complement factor I (CFI) associated with hemolytic uremic syndrome
Mol. Immunol.
45
95-105
2008
Homo sapiens (P05156)
Manually annotated by BRENDA team
Chan, M.R.; Thomas, C.P.; Torrealba, J.R.; Djamali, A.; Fernandez, L.A.; Nishimura, C.J.; Smith, R.J.; Samaniego, M.D.
Recurrent atypical hemolytic uremic syndrome associated with factor I mutation in a living related renal transplant recipient
Am. J. Kidney Dis.
53
321-326
2009
Homo sapiens
Manually annotated by BRENDA team
Fagerness, J.A.; Maller, J.B.; Neale, B.M.; Reynolds, R.C.; Daly, M.J.; Seddon, J.M.
Variation near complement factor I is associated with risk of advanced AMD
Eur. J. Hum. Genet.
17
100-104
2009
Homo sapiens
Manually annotated by BRENDA team
Nilsson, S.C.; Trouw, L.A.; Renault, N.; Miteva, M.A.; Genel, F.; Zelazko, M.; Marquart, H.; Muller, K.; Sjoeholm, A.G.; Truedsson, L.; Villoutreix, B.O.; Blom, A.M.
Genetic, molecular and functional analyses of complement factor I deficiency
Eur. J. Immunol.
39
310-323
2009
Homo sapiens
Manually annotated by BRENDA team
Yuasa, I.; Nakagawa, M.; Umetsu, K.; Harihara, S.; Matsusue, A.; Nishimukai, H.; Fukumori, Y.; Saitou, N.; Park, K.S.; Jin, F.; Lucotte, G.; Chattopadhyay, P.K.; Henke, L.; Henke, J.
Molecular basis of complement factor I (CFI) polymorphism: one of two polymorphic suballeles responsible for CFI A is Japanese-specific
J. Hum. Genet.
53
1016-1021
2008
Homo sapiens
Manually annotated by BRENDA team
Wang, J.; Ohno-Matsui, K.; Yoshida, T.; Kojima, A.; Shimada, N.; Nakahama, K.; Safranova, O.; Iwata, N.; Saido, T.C.; Mochizuki, M.; Morita, I.
Altered function of factor I caused by amyloid beta: implication for pathogenesis of age-related macular degeneration from Drusen
J. Immunol.
181
712-720
2008
Homo sapiens, Mus musculus
Manually annotated by BRENDA team
Hair, P.S.; Ward, M.D.; Semmes, O.J.; Foster, T.J.; Cunnion, K.M.
Staphylococcus aureus clumping factor A binds to complement regulator factor I and increases factor I cleavage of C3b
J. Infect. Dis.
198
125-133
2008
Homo sapiens
Manually annotated by BRENDA team
Ponce-Castro, I.M.; Gonzalez-Rubio, C.; Delgado-Cervino, E.M.; Abarrategui-Garrido, C.; Fontan, G.; Sanchez-Corral, P.; Lopez-Trascasa, M.
Molecular characterization of Complement Factor I deficiency in two Spanish families
Mol. Immunol.
45
2764-2771
2008
Homo sapiens
Manually annotated by BRENDA team
Nakahata, K.; Matsunami, K.; Kobayashi, C.; Omori, T.; Xu, H.; Firdawes, S.; Fukuzawa, M.; Miyagawa, S.
Analysis of the serine protease function of porcine factor I produced by liver cells for xenotransplantation
Transpl. Immunol.
19
30-36
2008
Homo sapiens (P05156), Homo sapiens, Sus scrofa
Manually annotated by BRENDA team
Nilsson, S.C.; Kalchishkova, N.; Trouw, L.A.; Fremeaux-Bacchi, V.; Villoutreix, B.O.; Blom, A.M.
Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or altered function of factor I
Eur. J. Immunol.
40
172-185
2010
Homo sapiens
Manually annotated by BRENDA team
Hair, P.S.; Echague, C.G.; Sholl, A.M.; Watkins, J.A.; Geoghegan, J.A.; Foster, T.J.; Cunnion, K.M.
Clumping factor A interaction with complement factor I increases C3b cleavage on the bacterial surface of Staphylococcus aureus and decreases complement-mediated phagocytosis
Infect. Immun.
78
1717-1727
2010
Homo sapiens
Manually annotated by BRENDA team
Ennis, S.; Gibson, J.; Cree, A.; Collins, A.; Lotery, A.
Support for the involvement of complement factor I in age-related macular degeneration
Eur. J. Hum. Genet.
18
15-16
2010
Homo sapiens
Manually annotated by BRENDA team
Roversi, P.; Johnson, S.; Caesar, J.J.; McLean, F.; Leath, K.J.; Tsiftsoglou, S.A.; Morgan, B.P.; Harris, C.L.; Sim, R.B.; Lea, S.M.
Structural basis for complement factor I control and its disease-associated sequence polymorphisms
Proc. Natl. Acad. Sci. USA
108
12839-12844
2011
Homo sapiens
Manually annotated by BRENDA team
Sanchez-Gallego, J.I.; Groeneveld, T.W.; Krentz, S.; Nilsson, S.C.; Villoutreix, B.O.; Blom, A.M.
Analysis of binding sites on complement factor I using artificial N-linked glycosylation
J. Biol. Chem.
287
13572-13583
2012
Homo sapiens
Manually annotated by BRENDA team
Broderick, L.; Gandhi, C.; Mueller, J.L.; Putnam, C.D.; Shayan, K.; Giclas, P.C.; Peterson, K.S.; Aceves, S.S.; Sheets, R.M.; Peterson, B.M.; Newbury, R.O.; Hoffman, H.M.; Bastian, J.F.
Mutations of complement factor I and potential mechanisms of neuroinflammation in acute hemorrhagic leukoencephalitis
J. Clin. Immunol.
33
162-171
2013
Homo sapiens
Manually annotated by BRENDA team
Malm, S.; Jusko, M.; Eick, S.; Potempa, J.; Riesbeck, K.; Blom, A.M.
Acquisition of complement inhibitor serine protease factor I and its cofactors C4b-binding protein and factor H by Prevotella intermedia
PLoS ONE
7
e34852
2012
Homo sapiens
Manually annotated by BRENDA team
Okroj, M.; Holmquist, E.; Nilsson, E.; Anagnostaki, L.; Jirstroem, K.; Blom, A.M.
Local expression of complement factor I in breast cancer cells correlates with poor survival and recurrence
Cancer Immunol. Immunother.
64
467-478
2015
Homo sapiens
Manually annotated by BRENDA team
Kumar, J.; Yadav, V.; Phulera, S.; Kamble, A.; Gautam, A.; Panwar, H.; Sahu, A.
Species specificity of vaccinia virus complement control protein for the bovine classical pathway is governed primarily by direct interaction of its acidic residues with factor I
J. Virol.
91
e00668-17
2017
Bos taurus, Homo sapiens
Manually annotated by BRENDA team