P06681 (CO2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Complement C2
EC=3.4.21.43

Alternative name(s):
C3/C5 convertase

Cleaved into the following 2 chains:

1. Complement C2b fragment
2. Complement C2a fragment

Gene names

Name:

C2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	752 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Component C2 which is part of the classical pathway of the complement system is cleaved by activated factor C1 into two fragments: C2b and C2a. C2a, a serine protease, then combines with complement factor 4b to generate the C3 or C5 convertase.
Catalytic activity	Selective cleavage of Arg-|-Ser bond in complement component C3 alpha-chain to form C3a and C3b, and Arg-|-Xaa bond in complement component C5 alpha-chain to form C5a and C5b.
Subunit structure	C2a interacts with Schistosoma haematobium TOR (via N-terminal extracellular domain). This results in inhibition of the classical and lectin pathway of complement activation, probably due to interference with binding of C2a to C4b such that C3 convertase cannot be formed. This infers resistance to complement-mediated cell lysis, allowing parasite survival and infection. Ref.9
Subcellular location	Secreted.
Polymorphism	The variant Asp-318 is associated with a reduced risk of age-related macular degeneration (ARMD) [MIM:603075]. ARMD is a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world.
Involvement in disease	Defects in C2 are the cause of complement component 2 deficiency (C2D) [MIM:217000]. A deficiency of the complement classical pathway associated with the development of autoimmune disorders, mainly systemic lupus erythematosus. Skin and joint manifestations are common and renal disease is relatively rare. Patients with complement component 2 deficiency are also reported to have recurrent or invasive infections. Ref.16 Ref.17
Miscellaneous	C2 is a major histocompatibility complex class-III protein.
Sequence similarities	Belongs to the peptidase S1 family. Contains 1 peptidase S1 domain. Contains 3 Sushi (CCP/SCR) domains. Contains 1 VWFA domain.

Ontologies

Keywords
Biological process	Complement pathway Immunity Innate immunity
Cellular component	Secreted
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Repeat Signal Sushi
Molecular function	Hydrolase Protease Serine protease
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	complement activation, classical pathway Traceable author statement. Source: ProtInc innate immune response Traceable author statement. Source: Reactome proteolysis Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	extracellular space Traceable author statement. Source: ProtInc
Molecular function	serine-type endopeptidase activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 20

20

Ref.7 Ref.9

Chain

21 – 752

732

Complement C2

PRO_0000027610

Chain

21 – 243

223

Complement C2b fragment

PRO_0000027611

Chain

244 – 752

509

Complement C2a fragment

PRO_0000027612

Regions

Domain

22 – 86

65

Sushi 1

Domain

87 – 146

60

Sushi 2

Domain

149 – 206

58

Sushi 3

Domain

254 – 452

199

VWFA

Domain

464 – 744

281

Peptidase S1

Sites

Active site

507

1

Charge relay system By similarity

Active site

561

1

Charge relay system By similarity

Active site

679

1

Charge relay system By similarity

Amino acid modifications

Glycosylation

29

1

N-linked (GlcNAc...) Potential

Glycosylation

112

1

N-linked (GlcNAc...) Ref.14 Ref.15

Glycosylation

290

1

N-linked (GlcNAc...) Potential

Glycosylation

333

1

N-linked (GlcNAc...) Ref.14 Ref.15

Glycosylation

467

1

N-linked (GlcNAc...) Ref.14

Glycosylation

471

1

N-linked (GlcNAc...) Ref.14

Glycosylation

621

1

N-linked (GlcNAc...) Ref.14

Glycosylation

651

1

N-linked (GlcNAc...) Ref.14

Disulfide bond

24 ↔ 64

By similarity

Disulfide bond

51 ↔ 84

By similarity

Disulfide bond

89 ↔ 131

By similarity

Disulfide bond

117 ↔ 144

By similarity

Disulfide bond

151 ↔ 191

By similarity

Disulfide bond

177 ↔ 204

By similarity

Disulfide bond

492 ↔ 508

By similarity

Disulfide bond

675 ↔ 705

By similarity

Natural variations

Natural variant

131

1

C → Y in C2D. Ref.17

VAR_008544

Natural variant

209

1

S → F in C2D. Ref.16
Corresponds to variant rs28934590 [ dbSNP | Ensembl ].

VAR_008545

Natural variant

318

1

E → D. Ref.5 Ref.18
Corresponds to variant rs9332739 [ dbSNP | Ensembl ].

VAR_019158

Natural variant

464

1

G → R in C2D. Ref.16

VAR_008546

Natural variant

533

1

F → L.
Corresponds to variant rs1042664 [ dbSNP | Ensembl ].

VAR_011772

Natural variant

734

1

R → C. Ref.5
Corresponds to variant rs4151648 [ dbSNP | Ensembl ].

VAR_019159

Experimental info

Sequence conflict

30

1

I → L AA sequence Ref.7

Sequence conflict

34

1

T → S AA sequence Ref.7

Sequence conflict

249

1

R → S AA sequence Ref.7

Sequence conflict

253

1

L → K AA sequence Ref.7

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

752

Helix Strand Turn

Details...

Beta strand

249 – 260

12

Helix

267 – 284

18

Turn

285 – 287

3

Beta strand

291 – 306

16

Helix

311 – 314

4

Helix

316 – 324

9

Helix

328 – 331

4

Helix

339 – 357

19

Beta strand

359 – 361

3

Helix

362 – 365

4

Beta strand

367 – 375

9

Beta strand

381 – 383

3

Helix

386 – 395

10

Helix

403 – 405

3

Beta strand

406 – 413

8

Helix

420 – 426

7

Beta strand

436 – 440

5

Helix

442 – 451

10

Helix

474 – 477

4

Beta strand

481 – 485

5

Beta strand

492 – 504

13

Helix

506 – 509

4

Helix

515 – 517

3

Beta strand

519 – 522

4

Beta strand

531 – 533

3

Beta strand

535 – 540

6

Helix

546 – 552

7

Beta strand

563 – 569

7

Beta strand

574 – 576

3

Helix

586 – 591

6

Helix

600 – 607

8

Beta strand

610 – 618

9

Beta strand

623 – 630

8

Helix

632 – 639

8

Helix

640 – 644

5

Helix

655 – 657

3

Beta strand

663 – 666

4

Helix

676 – 678

3

Beta strand

682 – 687

6

Beta strand

690 – 701

12

Turn

704 – 707

4

Beta strand

720 – 723

4

Beta strand

727 – 731

5

Helix

732 – 735

4

Helix

736 – 743

8

Turn

744 – 746

3

Sequences

	Sequence		Length	Mass (Da)
	P06681 [UniParc]. Last modified December 15, 1998. Version 2. Checksum: 5A96A13E700CF444	FASTA	752	83,268
	10 20 30 40 50 60 MGPLMVLFCL LFLYPGLADS APSCPQNVNI SGGTFTLSHG WAPGSLLTYS CPQGLYPSPA 70 80 90 100 110 120 SRLCKSSGQW QTPGATRSLS KAVCKPVRCP APVSFENGIY TPRLGSYPVG GNVSFECEDG 130 140 150 160 170 180 FILRGSPVRQ CRPNGMWDGE TAVCDNGAGH CPNPGISLGA VRTGFRFGHG DKVRYRCSSN 190 200 210 220 230 240 LVLTGSSERE CQGNGVWSGT EPICRQPYSY DFPEDVAPAL GTSFSHMLGA TNPTQKTKES 250 260 270 280 290 300 LGRKIQIQRS GHLNLYLLLD CSQSVSENDF LIFKESASLM VDRIFSFEIN VSVAIITFAS 310 320 330 340 350 360 EPKVLMSVLN DNSRDMTEVI SSLENANYKD HENGTGTNTY AALNSVYLMM NNQMRLLGME 370 380 390 400 410 420 TMAWQEIRHA IILLTDGKSN MGGSPKTAVD HIREILNINQ KRNDYLDIYA IGVGKLDVDW 430 440 450 460 470 480 RELNELGSKK DGERHAFILQ DTKALHQVFE HMLDVSKLTD TICGVGNMSA NASDQERTPW 490 500 510 520 530 540 HVTIKPKSQE TCRGALISDQ WVLTAAHCFR DGNDHSLWRV NVGDPKSQWG KEFLIEKAVI 550 560 570 580 590 600 SPGFDVFAKK NQGILEFYGD DIALLKLAQK VKMSTHARPI CLPCTMEANL ALRRPQGSTC 610 620 630 640 650 660 RDHENELLNK QSVPAHFVAL NGSKLNINLK MGVEWTSCAE VVSQEKTMFP NLTDVREVVT 670 680 690 700 710 720 DQFLCSGTQE DESPCKGESG GAVFLERRFR FFQVGLVSWG LYNPCLGSAD KNSRKRAPRS 730 740 750 KVPPPRDFHI NLFRMQPWLR QHLGDVLNFL PL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Primary structure of human complement component C2. Homology to two unrelated protein families." Bentley D.R. Biochem. J. 239:339-345(1986) [PubMed: 2949737] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Liver.
[2]	"cDNA cloning and expression of human complement component C2." Horiuchi T., Macon K.J., Kidd V.J., Volanakis J.E. J. Immunol. 142:2105-2111(1989) [PubMed: 2493504] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Liver.
[3]	"Structure of the human C2 gene." Ishii Y., Zhu Z.B., Macon K.J., Volanakis J.E. J. Immunol. 151:170-174(1993) [PubMed: 8326124] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"Sequence determination of 300 kilobases of the human class III MHC locus." Rowen L., Dankers C., Baskin D., Faust J., Loretz C., Ahearn M.E., Banta A., Swartzell S., Smith T.M., Spies T., Hood L. Submitted (SEP-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	SeattleSNPs variation discovery resource Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS ASP-318 AND CYS-734.
[6]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain.
[7]	"The purification and properties of the second component of guinea-pig complement." Kerr M.A., Gagnon J. Biochem. J. 205:59-67(1982) [PubMed: 6922702] [Abstract] Cited for: PROTEIN SEQUENCE OF 21-46 AND 244-256.
[8]	"DNA polymorphism of the C2 locus." Bentley D.R., Campbell R.D., Cross S.J. Immunogenetics 22:377-390(1985) [PubMed: 2997031] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 21-46.
[9]	"A Schistosoma protein, Sh-TOR, is a novel inhibitor of complement which binds human C2." Inal J.M., Sim R.B. FEBS Lett. 470:131-134(2000) [PubMed: 10734221] [Abstract] Cited for: PROTEIN SEQUENCE OF 21-28, INTERACTION WITH SCHISTOSOMA HAEMATOBIUM TOR.
[10]	"Structure and activation of complement components C2 and factor B." Gagnon J. Philos. Trans. R. Soc. Lond., B, Biol. Sci. 306:301-309(1984) [PubMed: 6149575] [Abstract] Cited for: PROTEIN SEQUENCE OF 137-171; 454-466 AND 574-717.
[11]	"The reaction of iodine and thiol-blocking reagents with human complement components C2 and factor B. Purification and N-terminal amino acid sequence of a peptide from C2a containing a free thiol group." Parkes C., Gagnon J., Kerr M.A. Biochem. J. 213:201-209(1983) [PubMed: 6555044] [Abstract] Cited for: PROTEIN SEQUENCE OF 244-269.
[12]	"Isolation of cDNA clones for human complement component C2." Bentley D.R., Porter R.R. Proc. Natl. Acad. Sci. U.S.A. 81:1212-1215(1984) [PubMed: 6199794] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 588-717.
[13]	"Cell-specific expression of the human complement protein factor B gene: evidence for the role of two distinct 5'-flanking elements." Wu L.C., Morley B.J., Campbell R.D. Cell 48:331-342(1987) [PubMed: 3643061] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 694-752.
[14]	"Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry." Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J., Smith R.D. J. Proteome Res. 4:2070-2080(2005) [PubMed: 16335952] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-112; ASN-333; ASN-467; ASN-471; ASN-621 AND ASN-651, MASS SPECTROMETRY. Tissue: Plasma.
[15]	"Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry." Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H. J. Proteome Res. 8:651-661(2009) [PubMed: 19159218] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-112 AND ASN-333, MASS SPECTROMETRY. Tissue: Liver.
[16]	"Type II human complement C2 deficiency. Allele-specific amino acid substitutions (Ser189 --> Phe; Gly444 --> Arg) cause impaired C2 secretion." Wetsel R.A., Kulics J., Lokki M.L., Kiepiela P., Akama H., Johnson C.A., Densen P., Colten H.R. J. Biol. Chem. 271:5824-5831(1996) [PubMed: 8621452] [Abstract] Cited for: VARIANTS C2D PHE-209 AND ARG-464.
[17]	"A novel type II complement C2 deficiency allele in an African-American family." Zhu Z.B., Atkinson T.P., Volanakis J.E. J. Immunol. 161:578-584(1998) [PubMed: 9670930] [Abstract] Cited for: VARIANT C2D TYR-131.
[18]	"Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration." Gold B., Merriam J.E., Zernant J., Hancox L.S., Taiber A.J., Gehrs K., Cramer K., Neel J., Bergeron J., Barile G.R., Smith R.T., Hageman G.S., Dean M., Allikmets R. Nat. Genet. 38:458-462(2006) [PubMed: 16518403] [Abstract] Cited for: VARIANT ASP-318, INVOLVEMENT IN REDUCED RISK OF ARMD.
+	Additional computationally mapped references.

Web resources

C2base

C2 mutation db

SeattleSNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X04481 mRNA. Translation: CAA28169.1.
M26301 mRNA. Translation: AAA35614.1.
L09708, L09706, L09707 Genomic DNA. Translation: AAB97607.1.
AF019413 Genomic DNA. Translation: AAB67975.1.
AY349611 Genomic DNA. Translation: AAQ15273.1.
BC043484 mRNA. Translation: AAH43484.1.
M15549 Genomic DNA. Translation: AAA59649.1.
M15082 Genomic DNA. Translation: AAA59624.1.

IPI

IPI00303963.

PIR

C2HU. A25971.

RefSeq

NP_000054.2. NM_000063.4.

UniGene

Hs.408903.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2I6Q	X-ray	2.10	A	244-752	[»]
2I6S	X-ray	2.70	A	244-752	[»]
2ODP	X-ray	1.90	A	244-752	[»]
2ODQ	X-ray	2.30	A	244-752	[»]
3ERB	X-ray	1.80	A	21-243	[»]

ProteinModelPortal

P06681.

SMR

P06681. Positions 23-217, 244-752.

ModBase

Search...

Protein-protein interaction databases

IntAct

P06681. 1 interaction.

STRING

P06681.

Protein family/group databases

MEROPS

S01.194.

Polymorphism databases

DMDM

3915642.

Proteomic databases

PRIDE

P06681.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000299367; ENSP00000299367; ENSG00000166278.
ENST00000375510; ENSP00000364660; ENSG00000204364.
ENST00000383362; ENSP00000372853; ENSG00000206372.
ENST00000411803; ENSP00000402278; ENSG00000235696.
ENST00000413548; ENSP00000407961; ENSG00000231543.
ENST00000416252; ENSP00000405800; ENSG00000235017.
ENST00000448206; ENSP00000392835; ENSG00000226560.

GeneID

717.

KEGG

hsa:717.

UCSC

uc003nyf.1. human.

Organism-specific databases

CTD

717.

GeneCards

GC06P031865.

HGNC

HGNC:1248. C2.

HPA

CAB016775.

MIM

217000. phenotype.
603075. phenotype.
613927. gene.

neXtProt

NX_P06681.

Orphanet

169147. Immunodeficiency due to an early component of complement deficiency.

GenAtlas

Search...

Phylogenomic databases

HOVERGEN

HBG002567.

InParanoid

P06681.

OMA

LMVDRIF.

OrthoDB

EOG45DWP0.

PhylomeDB

P06681.

Enzyme and pathway databases

Reactome

REACT_6900. Immune System.

Gene expression databases

Bgee

P06681.

CleanEx

HS_C2.

Genevestigator

P06681.

GermOnline

ENSG00000204364. Homo sapiens.

Family and domain databases

InterPro

IPR011360. Compl_C2_B.
IPR016060. Complement_control_module.
IPR009003. Pept_cys/ser_Trypsin-like.
IPR018114. Peptidase_S1/S6_AS.
IPR001254. Peptidase_S1_S6.
IPR001314. Peptidase_S1A.
IPR000436. Sushi_SCR_CCP.
IPR002035. VWF_A.
[Graphical view]

Gene3D

G3DSA:2.10.70.10. Complement_control_module. 3 hits.

KO

K01332.

Pfam

PF00084. Sushi. 2 hits.
PF00089. Trypsin. 1 hit.
PF00092. VWA. 1 hit.
[Graphical view]

PIRSF

PIRSF001154. Compl_C2_B. 1 hit.

PRINTS

PR00722. CHYMOTRYPSIN.

SMART

SM00032. CCP. 3 hits.
SM00020. Tryp_SPc. 1 hit.
SM00327. VWA. 1 hit.
[Graphical view]

SUPFAM

SSF57535. Complement_control_module. 3 hits.
SSF50494. Pept_Ser_Cys. 1 hit.

PROSITE

PS50923. SUSHI. 3 hits.
PS50240. TRYPSIN_DOM. 1 hit.
PS00134. TRYPSIN_HIS. 1 hit.
PS00135. TRYPSIN_SER. 1 hit.
PS50234. VWFA. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

NextBio

2918.

PMAP-CutDB

P06681.

SOURCE

Search...

Entry information

Entry name

CO2_HUMAN

Accession

Primary (citable) accession number: P06681
Secondary accession number(s): O19694, Q13904

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 1, 1988
Last sequence update:	December 15, 1998
Last modified:	January 25, 2012
This is version 147 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.