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Information on EC 3.4.21.41 - complement subcomponent C1r
for references in articles please use BRENDA:EC3.4.21.41
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EC Tree 3 Hydrolases
3.4 Acting on peptide bonds (peptidases)
3.4.21 Serine endopeptidases
3.4.21.41 complement subcomponent C1r
IUBMB Comments
Activated from proenzyme C1r in plasma during activation of the complement system by the "classical" route. In peptidase family S1 (trypsin family)
The enzyme appears in viruses and cellular organisms
Synonyms
proteases c1r, c1r-lp, xolloid, c1r protease, complement subcomponent c1r, complement c1r subcomponent-like protein, complement protease c1r, c1r serine protease, serine protease c1r, multiprotein complex c1, more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
activated complement C1r
-
-
-
-
C1r
C1rbar-esterase
-
-
-
-
complement C1r, activated
-
-
-
-
multiprotein complex C1
the multiprotein complex C1 is formed from the recognition subcomponent C1q and a tetramer of proteases C1r2C1s2
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Selective cleavage of Lys(or Arg)-/-Ile bond in complement subcomponent C1s to form C_overbar_1s_ (EC 3.4.21.42)
EC 3.4.21.42
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-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
endopeptidase
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CAS REGISTRY NUMBER
COMMENTARY
80295-69-8
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
acetyl-Arg methyl ester + H2O
acetyl-Arg + methanol
-
Substrates: -
Products: -
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?
benzyloxycarbonyl-Gly-Arg-thiobenzyl ester + H2O
?
-
Substrates: -
Products: -
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?
benzyloxycarbonyl-Lys-thiobenzyl ester + H2O
benzyloxycarbonyl-Lys + phenylmethanethiol
-
Substrates: -
Products: -
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?
chordin + H2O
?
-
Substrates: C-terminal domains CUB1 and CUB2 are required for the ventralizing activity of Xld and for its ability to cleave chordin
Products: -
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?
MASP-3 K448Q zymogen + H2O
active MASP-3 protein + ?
Substrates: poor activity with the wild-type MASP-3
Products: -
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?
N-acetyl-Arg methyl ester + H2O
N-acetyl-Arg + methanol
-
Substrates: -
Products: -
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?
N-acetyl-Gly-Lys methyl ester + H2O
N-acetyl-Gly-Lys + methanol
-
Substrates: -
Products: -
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?
N-benzyloxycarbonyl-Gly-Arg thiobenzyl ester + H2O
?
-
Substrates: -
Products: -
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?
N-carbobenzoxy-Lys-p-nitrophenyl ester + H2O
N-carbobenzoxy-Lys + 4-nitrophenyl
-
Substrates: -
Products: -
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?
N-carbobenzoxy-Tyr-p-nitrophenyl ester + H2O
N-carbobenzoxy-Tyr + 4-nitrophenol
-
Substrates: -
Products: -
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?
prohaptoglobin + H2O
haptoglobin + ?
Substrates: the enzyme cleaves prohaptoglobin after arginine R102 in variants Hp1F and Hp1S or after R161 in variant Hp2FS
Products: -
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?
complement C1q zymogen + H2O
active complement C1q + ?
Substrates: -
Products: -
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?
complement C1q zymogen + H2O
active complement C1q + ?
Substrates: no or reduced activity with substrate mutants K59A, K61A, K58A, and K58A/K59A/K61A
Products: -
Products: -
?
complement component C1s
?
-
Substrates: binding of C1 to activator is mediated by C1q and triggers activation of proenzyme C1r into an active protease C1rbar, which in turn activates C1s, thereby initiating the classical pathway of complement
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?
complement component C1s
?
-
Substrates: regulation of the synthesis
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?
complement component C1s
?
-
Substrates: activates the proenzyme form of C1s by limited proteolysis
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?
complement component C1s + H2O
activated complement component C1s + ?
Substrates: -
Products: -
Products: -
?
complement component C1s + H2O
activated complement component C1s + ?
-
Substrates: the enzyme is part of the Ca2+-dependent tetramer C1s-C1r-C1r-C1s, termed as C1 complex, which is associated with the recognition molecule C1q, autoactivation of C1r, which then activates proenzyme C1s through cleavage at an Arg-Ile bond in the serine domain, C1r is active in the classical pathway of the complement system
Products: -
Products: -
?
complement component C1s + H2O
activated complement component C1s + ?
Substrates: the enzyme is part of the Ca2+-dependent tetramer C1s-C1r-C1r-C1s, termed as C1 complex, which is associated with the recognition molecule C1q, autoactivation of C1r, which then activates proenzyme C1s through cleavage at an Arg-Ile bond in the serine domain, C1r is active in the classical pathway of the complement system
Products: -
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?
complement component C1s + H2O
activated complement component C1s + ?
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Substrates: the enzyme is part of the Ca2+-dependent tetramer C1s-C1r-C1r-C1s, termed as C1 complex, which is associated with the recognition molecule C1q, autoactivation of C1r, which then activates proenzyme C1s through cleavage at an Arg-Ile bond in the serine domain, C1r is active in the classical pathway of the complement system, interaction anaylsis of the C1 complex and regulatory proteins, overview
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?
complement component C1s + H2O
activated complement component C1s + ?
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Substrates: C1r cleaves proenzyme C1s at an Arg-Ile bond in the serine domain
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?
complement component C1s + H2O
activated complement component C1s + ?
Substrates: C1r cleaves proenzyme C1s at an Arg-Ile bond in the serine domain, enzyme-product binding structure, overview
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?
complement component C1s + H2O
activated complement component C1s + ?
Substrates: -
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?
complement component C1s + H2O
activated complement component C1s + ?
Substrates: -
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?
complement component C1s + H2O
complement component C1sbar
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Substrates: -
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?
complement component C1s + H2O
complement component C1sbar
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Substrates: cleavage of a single Arg-Ile or Lys-Ile bond in C1s
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?
complement component C1s + H2O
complement component C1sbar
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Substrates: cleavage of a single Arg-Ile bond in the sequence Lys-Gln-Arg-Ile-Ile-Gly
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?
complement component C1s + H2O
complement component C1sbar
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Substrates: C1rbar does not hydrolyze any amino acid ester tested nor any protein substrate except subcomponent C1s
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?
complement component C1s + H2O
complement component C1sbar
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Substrates: C1R and its activated fragments all cleave C1s, in the order of increasing efficiency: C21r, CCP1/2-SP, CCP2-SP. CCP1 is not involved in C1s recognition
Products: -
Products: -
?
zymogen C1s + H2O
active C1s protease + ?
Substrates: the enzyme is active with the substrate fragment consisting of complement control protein domains, CCP1 and CCP2, plus serine protease domain of wild-type and mutant Q462N, Q462G, I464A, and Q462N/I464A forms of C1s, mutant Q462N/I464A substrate gives very low activity
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?
additional information
?
-
-
Substrates: the ability of autoactivation of C1r and C1s cleavage activity is an inherent property of the SP domain
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?
additional information
?
-
Substrates: the enzyme recognizes the a short collagen-like peptide containing the sequence Hyp-Gly-Lys-Leu-Gly-Pro
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?
additional information
?
-
Substrates: the residues found in the activation loop of the zymogens capable of being activated by enzyme C1r play a major role in recognition of the active site of enzyme C1r
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?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
complement C1q zymogen + H2O
active complement C1q + ?
Substrates: -
Products: -
Products: -
?
prohaptoglobin + H2O
haptoglobin + ?
Substrates: the enzyme cleaves prohaptoglobin after arginine R102 in variants Hp1F and Hp1S or after R161 in variant Hp2FS
Products: -
Products: -
?
complement component C1s
?
-
Substrates: binding of C1 to activator is mediated by C1q and triggers activation of proenzyme C1r into an active protease C1rbar, which in turn activates C1s, thereby initiating the classical pathway of complement
Products: -
Products: -
?
complement component C1s
?
-
Substrates: regulation of the synthesis
Products: -
Products: -
?
complement component C1s
?
-
Substrates: activates the proenzyme form of C1s by limited proteolysis
Products: -
Products: -
?
complement component C1s + H2O
activated complement component C1s + ?
Substrates: -
Products: -
Products: -
?
complement component C1s + H2O
activated complement component C1s + ?
-
Substrates: the enzyme is part of the Ca2+-dependent tetramer C1s-C1r-C1r-C1s, termed as C1 complex, which is associated with the recognition molecule C1q, autoactivation of C1r, which then activates proenzyme C1s through cleavage at an Arg-Ile bond in the serine domain, C1r is active in the classical pathway of the complement system
Products: -
Products: -
?
complement component C1s + H2O
activated complement component C1s + ?
Substrates: the enzyme is part of the Ca2+-dependent tetramer C1s-C1r-C1r-C1s, termed as C1 complex, which is associated with the recognition molecule C1q, autoactivation of C1r, which then activates proenzyme C1s through cleavage at an Arg-Ile bond in the serine domain, C1r is active in the classical pathway of the complement system
Products: -
Products: -
?
complement component C1s + H2O
activated complement component C1s + ?
-
Substrates: the enzyme is part of the Ca2+-dependent tetramer C1s-C1r-C1r-C1s, termed as C1 complex, which is associated with the recognition molecule C1q, autoactivation of C1r, which then activates proenzyme C1s through cleavage at an Arg-Ile bond in the serine domain, C1r is active in the classical pathway of the complement system, interaction anaylsis of the C1 complex and regulatory proteins, overview
Products: -
Products: -
?
complement component C1s + H2O
activated complement component C1s + ?
Substrates: -
Products: -
Products: -
?
complement component C1s + H2O
activated complement component C1s + ?
Substrates: -
Products: -
Products: -
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
Ca2+
-
the NH2-terminal alpha fragment of the enzyme contains one high affinity Ca2+ binding site
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
C1-inhibitor
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regulates the classical and the lectin complement pathway inhibiting complement components C1r and C1s, and MASP-2, factor XIa, Factor XIIa, and plasma kallikrein, mechanism, overview
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C1INH
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sole inhibitor of the activated proteases C1r and C1s. Hereditary angioedema results from functional deficiency of the C1 inhibitor (C1INH) protein, which plays a key role in the classical pathway of complement activation
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C1 inhibitor
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during complex formation, C1 inhibitor dissociates C1r and C1s from the activated C1 macromolecule, a process that is determined primarily by the interaction with C1r
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C1bar-inhibitor
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Ca2+ decreases the rate at which C1rbar complexes with C1bar-inhibitor. C1rbar-(C1bar-inhibitor) interaction is accelerated by heparin. Flufenamic acid inhibits the action of the inhibitor
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additional information
-
above 0.0005 mM C1rbar the enzyme aggregates with loss of activity
-
additional information
-
specific c-Jun amino-terminal kinase inhibitor and the MEK-1 inhibitor PD98059 do not regulate C1r mRNA expression, whereas JSH-23, which inhibits nuclear translocation of NF-kappaB decreases C1r expression selectively in MEF-2 cells
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
the recognition molecule C1q to the C1 complex triggers its autoactivation via C1r, the C-reactive protein, CRP, activates the C1 complex by binding to C1q
-
additional information
-
regulation of C1r by low-density lipoprotein receptor-related protein 1
-
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Carcinoma
Tumour serine proteases C1r and C1s as novel biomarkers and therapeutic targets in invasive sporadic and recessive dystrophic epidermolysis bullosa-associated cutaneous squamous cell carcinoma.
Carcinoma, Hepatocellular
Prohaptoglobin is proteolytically cleaved in the endoplasmic reticulum by the complement C1r-like protein.
Carcinoma, Squamous Cell
Tumour serine proteases C1r and C1s as novel biomarkers and therapeutic targets in invasive sporadic and recessive dystrophic epidermolysis bullosa-associated cutaneous squamous cell carcinoma.
Infections
Importance of the prime subsites of the C1s protease of the classical complement pathway for recognition of substrates.
Neoplasms
Tumour serine proteases C1r and C1s as novel biomarkers and therapeutic targets in invasive sporadic and recessive dystrophic epidermolysis bullosa-associated cutaneous squamous cell carcinoma.
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000022
zymogen C1s
pH 7.4, 37Ā°C, substrate is a fragment consisting of complement control protein domains, CCP1 and CCP2, plus serine
-
additional information
additional information
-
activated C1r and its wild-type CCP1/2-SP and CCP2-SP fragments all cleave acetyl-Gly-Lys-methyl ester with KM-values ranging from 1.3 mM to 2.1 mM
-
additional information
additional information
-
KM-values of the C1r fragments with benzyloxycarbonyl-Lys-thiobenzyl ester or benzyloxycarbonyl-Gly-Arg-thiobenzyl ester as substrate
-
additional information
additional information
-
kinetic interaction anaylsis of the C1 complex and regulatory proteins, e.g. the C-reactive protein, overview
-
additional information
additional information
kinetics of activation of C1s and MASP-3 mutants, overview
-
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0645
zymogen C1s
pH 7.4, 37Ā°C, substrate is a fragment consisting of complement control protein domains, CCP1 and CCP2, plus serine
-
additional information
additional information
-
activated C1r and its wild-type CCP1/2-SP and CCP2-SP fragments all cleave acetyl-Gly-Lys-methyl ester with turnover numbers ranging from 8.2 s to 9.2 s
-
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2900
zymogen C1s
pH 7.4, 37Ā°C, substrate is a fragment consisting of complement control protein domains, CCP1 and CCP2, plus serine
-
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
MEF-2 cell, low-density lipoprotein receptor-related protein 1-deficient macrophages show increased expression of C1r
brenda
-
C1r mRNA expression is significantly increased in RAW 264.7 cells in which low-density lipoprotein receptorĀrelated protein 1 is silenced
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
Highest Expressing Human Cell Lines
Cell Line LinksPlease wait a moment until the data is sorted. This message will disappear when the data is sorted.
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
binding residues are conserved in the CUB1 domains of C1r, MASP-1/-3, and MASP-2, indicating that the interaction mechanism is conserved in initiating complexes of the lectin and classical pathways
metabolism
physiological function
additional information
metabolism
C1r and C1s pro-enzymes form a heterotetrameric structure that associates with the recognition molecule, C1q, in the C1 complex
metabolism
complement is an important part of the immune system. It is initiated through three different pathways known as the classical, lectin, and alternative pathway. The multimolecular C1 complex of the classical pathway consists of a subcomponent, C1q, which binds to a tetramer comprising two C1r and two C1s proteases, EC 3.4.21.41 and EC 3.4.21.42, respectively
metabolism
hexameric complement C1q is a versatile recognition protein that senses a wide variety of immune and nonimmune ligands, including pathogens and altered self components, and triggers the classical complement pathway through activation of its associated proteases C1r and C1s, EC 3.4.21.42. Residues LysB61 and LysC58 each play a key role in the interaction with C1s-C1r-C1r-C1s, with LysA59 being involved to a lesser degree
physiological function
C1r is a zymogen, activation of C1 occurs when the C1q subcomponent binds to a pathogen via its globular heads resulting in autolytic activation of C1r followed, in turn, by C1r-mediated activation of C1s
physiological function
the large multicomponent assembly C1 complex, binds to immune complexes, protein modulators (e.g., C-reactive protein), and polyanionic structures on pathogens to initiate complement activation. Binding to pathogens induces a conformational change that drives activation of the zymogen proteases in stepwise fashion: C1r first autoactivates, then activates C1s. C1s subsequently cleaves substrates C4 and C4b-bound C2, to form the C3 convertase (C4b2a), the downstream component of the reaction cascade
physiological function
multiprotein complex C1 triggers the destruction of invading pathogens via lysis or by stimulation of innate and adaptive immune processes
additional information
subsite profiling of human C1r using a phage display library with a fixed P1 arginine, specificity determinants, overview. Gln and Ile residues at P2 and P1', respectively, are important for cleavage of phage displayed substrates, the enzyme displays considerable specificity at every position apart from P4, P3', and P4'
additional information
the C1s/C1r/C1r/C1s tetramer forms a complex with C1q by interacting with the stems. C1r is a homologous multidomain protease containing an N-terminal CUB module, an EGF-like module, a second CUB module, two complement control modules CCP, and a serine protease domain SP. The three domains that constitute the catalytic fragment of C1r (CCP1-CCP2-SP) readily form head-to-tail dimers. The CUB1-EGF-CUB2 fragments of C1r also dimerize. Interaction analysis and structure-function relationship, formation of the C1 complex, molecular dynamics simulations and thermodynamics, detailed overview
additional information
the large multicomponent assembly C1 complex is composed of a recognition subcomponent, C1q (460 kDa), and two serine protease subcomponents, C1r (90 kDa) and C1s (80 kDa) in a 1:2:2 ratio, with an overall molecular mass of about790 kDa. C1r is a modular protease with two N-terminal complement C1r/C1s, Uegf and bone morphogenetic protein-1(CUB) domains, separated by an epidermal growth factor (EGF)-ike domain, followed by two complement control modules (CCP) and a C-terminal serine protease (SP) domain
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
83000
-
2 * 83000, SDS-PAGE of reduced protein, gel filtration in 6 M guanidinium hydrochloride
85000
-
2 * 85000, the C1rbar subunits consist of one polypeptide chain of 56000 Da, A-chain, that is disulfide-linked to a 27000 Da B-chain, SDS-PAGE
90000
-
immunoblot analysis, in PEA-10 and B-41 cells, single-chain form, which is the zymogen
additional information
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
additional information
?
x * 69500, enzyme fused to maltose binding protein, SDS-PAGE
dimer
-
2 * 83000, SDS-PAGE of reduced protein, gel filtration in 6 M guanidinium hydrochloride
dimer
-
2 * 85000, the C1rbar subunits consist of one polypeptide chain of 56000 Da, A-chain, that is disulfide-linked to a 27000 Da B-chain, SDS-PAGE
dimer
-
CCP1 is essential to the assembly of the dimer, but formation of a stable dimer is not a prerequisite for self-activation
dimer
-
deletion of CCP1 domain from CCP1-CCP2-SP fragment results in the loss of the dimeric structure. Dimerization of C1r is not a prerequisite for autoactivation
additional information
-
the C1 complex comprises two loosely interacting subunits, C1q and the Ca2+-dependent C1s-C1r-C1r-C1s tetramer. Binding of C1 to activator is mediated by C1q and triggers activation of proenzyme C1r into an active protease C1rbar, which in turn activates C1s, thereby initiating the classical pathway of complement
additional information
-
on activation the single polypeptide chain of C1r is cleaved probably at a single position, the C1rbar subunits consist of 1 polypeptide chain of 56000 Da, A-chain, that is disulfide-linked to a 27000 Da B-chain
additional information
-
C1rbar and the proenzyme C1r are noncovalent dimers, the subunit of C1r has a MW of 53000-85000 Da, SDS-PAGE
additional information
C1r and C1s pro-enzymes form a heterotetrameric structure that associates with the recognition molecule, C1q, in the C1 complex
additional information
each C1r monomer consists of six domains, CUB1-EGF-CUB2-CCP1-CCP2-SP, i.e. an N-terminal CUB module, an EGF-like module, a second CUB module, two complement control modules CCP, and a serine protease domain SP. The three domains that constitute the catalytic fragment of C1r (CCP1-CCP2-SP) readily form head-to-tail dimers. The CUB1-EGF-CUB2 fragments of C1r also dimerize