P05156 (CFAI_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Complement factor I
EC=3.4.21.45

Alternative name(s):
C3B/C4B inactivator

Cleaved into the following 2 chains:

1. Complement factor I heavy chain
2. Complement factor I light chain

Gene names

Name:	CFI
Synonyms:	IF

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	583 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	Responsible for cleaving the alpha-chains of C4b and C3b in the presence of the cofactors C4-binding protein and factor H respectively.
Catalytic activity	Inactivates complement subcomponents C3b, iC3b and C4b by proteolytic cleavage.
Subunit structure	Heterodimer of a light and heavy chains linked by disulfide bonds.
Subcellular location	Secreted › extracellular space.
Tissue specificity	Plasma.
Involvement in disease	Defects in CFI are a cause of susceptibility to hemolytic uremic syndrome atypical type 3 (AHUS3) [MIM:612923]. An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Note=Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype. Ref.12 Ref.13 Ref.15 Ref.16 Defects in CFI are the cause of complement factor I deficiency (CFI deficiency) [MIM:610984]. CFI deficiency is an autosomal recessive condition associated with a propensity to pyogenic infections.
Sequence similarities	Belongs to the peptidase S1 family. Contains 1 Kazal-like domain. Contains 2 LDL-receptor class A domains. Contains 1 peptidase S1 domain. Contains 1 SRCR domain.
Sequence caution	The sequence CAA68416.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Ontologies

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

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 18

18

Chain

19 – 583

565

Complement factor I

PRO_0000027568

Chain

19 – 335

317

Complement factor I heavy chain

PRO_0000027569

Chain

340 – 583

244

Complement factor I light chain

PRO_0000027570

Regions

Domain

55 – 108

54

Kazal-like

Domain

114 – 212

99

SRCR

Domain

213 – 257

45

LDL-receptor class A 1

Domain

258 – 294

37

LDL-receptor class A 2

Domain

340 – 574

235

Peptidase S1

Sites

Active site

380

1

Charge relay system By similarity

Active site

429

1

Charge relay system By similarity

Active site

525

1

Charge relay system By similarity

Amino acid modifications

Glycosylation

70

1

N-linked (GlcNAc...) Ref.7

Glycosylation

103

1

N-linked (GlcNAc...) (complex) Ref.7 Ref.8 Ref.9

Glycosylation

177

1

N-linked (GlcNAc...) Ref.7

Glycosylation

464

1

N-linked (GlcNAc...) Ref.6 Ref.7

Glycosylation

494

1

N-linked (GlcNAc...) Potential

Glycosylation

536

1

N-linked (GlcNAc...) Ref.7

Disulfide bond

154 ↔ 214

By similarity

Disulfide bond

186 ↔ 196

By similarity

Disulfide bond

229 ↔ 247

By similarity

Disulfide bond

241 ↔ 256

By similarity

Disulfide bond

259 ↔ 271

By similarity

Disulfide bond

266 ↔ 284

By similarity

Disulfide bond

278 ↔ 293

By similarity

Disulfide bond

365 ↔ 381

By similarity

Disulfide bond

467 ↔ 531

By similarity

Disulfide bond

495 ↔ 510

By similarity

Disulfide bond

521 ↔ 550

By similarity

Natural variations

Natural variant

64

1

P → L in AHUS3. Ref.16

VAR_063665

Natural variant

119

1

G → R in AHUS3. Ref.16

VAR_063666

Natural variant

183

1

H → R in AHUS3. Ref.16

VAR_063667

Natural variant

243

1

G → D in CFI deficiency. Ref.14

VAR_034907

Natural variant

287

1

G → R in AHUS3. Ref.16

VAR_063668

Natural variant

300

1

T → A. Ref.1 Ref.2
Corresponds to variant rs11098044 [ dbSNP | Ensembl ].

VAR_034908

Natural variant

317

1

R → W in AHUS3. Ref.13

VAR_063669

Natural variant

340

1

I → T in AHUS3. Ref.15

VAR_030343

Natural variant

416

1

I → L in AHUS3. Ref.16

VAR_063670

Natural variant

418

1

H → L in CFI deficiency. Ref.10

VAR_026757

Natural variant

519

1

D → N in AHUS3. Ref.13

VAR_063671

Natural variant

522

1

K → T in AHUS3. Ref.16

VAR_063672

Natural variant

524

1

D → V in AHUS3. Ref.12

VAR_030344

Experimental info

Sequence conflict

558

1

V → F in AAA52455. Ref.2

Secondary structure

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583

Helix Strand Turn

Details...

Turn

34 – 36

3

Helix

43 – 45

3

Beta strand

52 – 55

4

Beta strand

58 – 61

4

Helix

64 – 66

3

Beta strand

74 – 76

3

Turn

77 – 79

3

Beta strand

80 – 84

5

Helix

85 – 94

10

Beta strand

100 – 105

6

Beta strand

113 – 118

6

Beta strand

124 – 130

7

Beta strand

138 – 140

3

Helix

147 – 156

10

Beta strand

173 – 175

3

Beta strand

182 – 185

4

Helix

193 – 195

3

Beta strand

196 – 199

4

Beta strand

211 – 214

4

Beta strand

242 – 244

3

Beta strand

247 – 258

12

Beta strand

260 – 262

3

Beta strand

264 – 266

3

Turn

267 – 269

3

Beta strand

270 – 272

3

Helix

274 – 276

3

Beta strand

279 – 281

3

Beta strand

284 – 286

3

Beta strand

290 – 292

3

Helix

312 – 319

8

Beta strand

356 – 362

7

Beta strand

368 – 371

4

Beta strand

374 – 377

4

Helix

379 – 382

4

Beta strand

390 – 393

4

Beta strand

409 – 417

9

Turn

423 – 425

3

Beta strand

432 – 435

4

Beta strand

439 – 442

4

Beta strand

466 – 470

5

Beta strand

486 – 491

6

Helix

496 – 499

4

Turn

505 – 507

3

Beta strand

508 – 513

6

Beta strand

528 – 532

5

Beta strand

538 – 546

9

Beta strand

557 – 561

5

Helix

562 – 565

4

Helix

566 – 572

7

Sequences

	Sequence		Length	Mass (Da)
	P05156 [UniParc]. Last modified January 11, 2011. Version 2. Checksum: F06070EFE6B572A1	FASTA	583	65,750
	10 20 30 40 50 60 MKLLHVFLLF LCFHLRFCKV TYTSQEDLVE KKCLAKKYTH LSCDKVFCQP WQRCIEGTCV 70 80 90 100 110 120 CKLPYQCPKN GTAVCATNRR SFPTYCQQKS LECLHPGTKF LNNGTCTAEG KFSVSLKHGN 130 140 150 160 170 180 TDSEGIVEVK LVDQDKTMFI CKSSWSMREA NVACLDLGFQ QGADTQRRFK LSDLSINSTE 190 200 210 220 230 240 CLHVHCRGLE TSLAECTFTK RRTMGYQDFA DVVCYTQKAD SPMDDFFQCV NGKYISQMKA 250 260 270 280 290 300 CDGINDCGDQ SDELCCKACQ GKGFHCKSGV CIPSQYQCNG EVDCITGEDE VGCAGFASVT 310 320 330 340 350 360 QEETEILTAD MDAERRRIKS LLPKLSCGVK NRMHIRRKRI VGGKRAQLGD LPWQVAIKDA 370 380 390 400 410 420 SGITCGGIYI GGCWILTAAH CLRASKTHRY QIWTTVVDWI HPDLKRIVIE YVDRIIFHEN 430 440 450 460 470 480 YNAGTYQNDI ALIEMKKDGN KKDCELPRSI PACVPWSPYL FQPNDTCIVS GWGREKDNER 490 500 510 520 530 540 VFSLQWGEVK LISNCSKFYG NRFYEKEMEC AGTYDGSIDA CKGDSGGPLV CMDANNVTYV 550 560 570 580 WGVVSWGENC GKPEFPGVYT KVANYFDWIS YHVGRPFISQ YNV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Characterization of primary amino acid sequence of human complement control protein factor I from an analysis of cDNA clones." Catterall C.F., Lyons A., Sim R.M., Day A.J., Harris T.J.R. Biochem. J. 242:849-856(1987) [PubMed: 2954545] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT ALA-300. Tissue: Liver.
[2]	"Human complement factor I: analysis of cDNA-derived primary structure and assignment of its gene to chromosome 4." Goldberger G., Bruns G.A.P., Rits M., Edge M.D., Kwiatkowski D.J. J. Biol. Chem. 262:10065-10071(1987) [PubMed: 2956252] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT ALA-300.
[3]	"Generation and annotation of the DNA sequences of human chromosomes 2 and 4." Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K. Nature 434:724-731(2005) [PubMed: 15815621] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"Cloning and characterization of the promoter for the human complement factor I (C3b/C4b inactivator) gene." Minta J.O., Fung M., Turner S., Eren R., Zemach L., Rits M., Goldberger G. Gene 208:17-24(1998) [PubMed: 9479036] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-18. Tissue: Liver.
[5]	"Beta-sheet secondary structure of an LDL receptor domain from complement factor I by consensus structure predictions and spectroscopy." Ullman C.G., Haris P.I., Smith K.F., Sim R.B., Emery V.C., Perkins S.J. FEBS Lett. 371:199-203(1995) [PubMed: 7672128] [Abstract] Cited for: PROTEIN SEQUENCE OF 258-269.
[6]	"Screening for N-glycosylated proteins by liquid chromatography mass spectrometry." Bunkenborg J., Pilch B.J., Podtelejnikov A.V., Wisniewski J.R. Proteomics 4:454-465(2004) [PubMed: 14760718] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-464, MASS SPECTROMETRY. Tissue: Plasma.
[7]	"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-70; ASN-103; ASN-177; ASN-464 AND ASN-536, MASS SPECTROMETRY. Tissue: Plasma.
[8]	"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-103, MASS SPECTROMETRY. Tissue: Liver.
[9]	"Enrichment of glycopeptides for glycan structure and attachment site identification." Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E., Brinkmalm G., Larson G. Nat. Methods 6:809-811(2009) [PubMed: 19838169] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-103, STRUCTURE OF CARBOHYDRATES, MASS SPECTROMETRY. Tissue: Cerebrospinal fluid.
[10]	"The molecular basis of hereditary complement factor I deficiency." Vyse T.J., Morley B.J., Bartok I., Theodoridis E.L., Davies K.A., Webster A.D.B., Walport M.J. J. Clin. Invest. 97:925-933(1996) [PubMed: 8613545] [Abstract] Cited for: VARIANT CFI DEFICIENCY LEU-418.
[11]	"Molecular characterization of homozygous hereditary factor I deficiency." Baracho G.V., Nudelman V., Isaac L. Clin. Exp. Immunol. 131:280-286(2003) [PubMed: 12562389] [Abstract] Cited for: INVOLVEMENT IN CFI DEFICIENCY.
[12]	"Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome." Fremeaux-Bacchi V., Dragon-Durey M.-A., Blouin J., Vigneau C., Kuypers D., Boudailliez B., Loirat C., Rondeau E., Fridman W.H. J. Med. Genet. 41:E84-E84(2004) [PubMed: 15173250] [Abstract] Cited for: VARIANT AHUS3 VAL-524.
[13]	"Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome." The international registry of recurrent and familial HUS/TTP Caprioli J., Noris M., Brioschi S., Pianetti G., Castelletti F., Bettinaglio P., Mele C., Bresin E., Cassis L., Gamba S., Porrati F., Bucchioni S., Monteferrante G., Fang C.J., Liszewski M.K., Kavanagh D., Atkinson J.P., Remuzzi G. Blood 108:1267-1279(2006) [PubMed: 16621965] [Abstract] Cited for: VARIANTS AHUS3 TRP-317 AND ASN-519.
[14]	"Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome." Servais A., Fremeaux-Bacchi V., Lequintrec M., Salomon R., Blouin J., Knebelmann B., Gruenfeld J.-P., Lesavre P., Noeel L.-H., Fakhouri F. J. Med. Genet. 44:193-199(2007) [PubMed: 17018561] [Abstract] Cited for: VARIANT CFI DEFICIENCY ASP-243.
[15]	"A missense mutation in factor I (IF) predisposes to atypical haemolytic uraemic syndrome." Geelen J., van den Dries K., Roos A., van de Kar N., de Kat Angelino C., Klasen I., Monnens L., van den Heuvel L. Pediatr. Nephrol. 22:371-375(2007) [PubMed: 17106690] [Abstract] Cited for: VARIANT AHUS3 THR-340.
[16]	"Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome." Maga T.K., Nishimura C.J., Weaver A.E., Frees K.L., Smith R.J.H. Hum. Mutat. 31:E1445-E1460(2010) [PubMed: 20513133] [Abstract] Cited for: VARIANTS AHUS3 LEU-64; ARG-119; ARG-183; ARG-287; LEU-416 AND THR-522.
+	Additional computationally mapped references.

Web resources

CFIbase

CFI mutation db

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

Y00318 mRNA. Translation: CAA68416.1. Different initiation.
J02770 mRNA. Translation: AAA52455.1.
AC126283 Genomic DNA. No translation available.
AF005095 Genomic DNA. Translation: AAC08733.2.

IPI

IPI00291867.

PIR

A29154.

RefSeq

NP_000195.2. NM_000204.3.

UniGene

Hs.312485.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2XRC	X-ray	2.69	A/B/C/D	19-583	[»]

ProteinModelPortal

P05156.

SMR

P05156. Positions 27-583.

ModBase

Search...

Protein-protein interaction databases

STRING

P05156.

Protein family/group databases

MEROPS

S01.199.

Polymorphism databases

DMDM

116133.

2D gel databases

SWISS-2DPAGE

P05156.

Proteomic databases

PeptideAtlas

P05156.

PRIDE

P05156.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000394634; ENSP00000378130; ENSG00000205403.

GeneID

3426.

KEGG

hsa:3426.

UCSC

uc003hzr.2. human.

Organism-specific databases

CTD

3426.

GeneCards

GC04M110661.

H-InvDB

HIX0004438.

HGNC

HGNC:5394. CFI.

HPA

CAB016777.
HPA001143.
HPA024061.

MIM

217030. gene.
610984. phenotype.
612923. phenotype.

neXtProt

NX_P05156.

Orphanet

93580. Atypical hemolytic uremic syndrome with I factor anomaly.
93559. C3 deposition glomerulonephritis without proliferation.
244275. De novo thrombotic microangiopathy after kidney transplantation.
244242. HELLP syndrome.
200418. Immunodeficiency with factor I anomaly.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG05272.

HOVERGEN

HBG005311.

Enzyme and pathway databases

BRENDA

3.4.21.45. 2681.

Gene expression databases

ArrayExpress

P05156.

Bgee

P05156.

CleanEx

HS_CFI.

Genevestigator

P05156.

GermOnline

ENSG00000205403. Homo sapiens.

Family and domain databases

InterPro

IPR003884. FacI_MAC.
IPR023415. LDLR_class-A_CS.
IPR002172. LDrepeatLR_classA_rpt.
IPR009003. Pept_cys/ser_Trypsin-like.
IPR018114. Peptidase_S1/S6_AS.
IPR001254. Peptidase_S1_S6.
IPR001314. Peptidase_S1A.
IPR001190. Srcr_rcpt.
IPR017448. Srcr_rcpt-rel.
[Graphical view]

Gene3D

G3DSA:4.10.400.10. LDL_rcpt_classA_cys-rich. 2 hits.

KO

K01333.

Pfam

PF00057. Ldl_recept_a. 2 hits.
PF00530. SRCR. 1 hit.
PF00089. Trypsin. 1 hit.
[Graphical view]

PRINTS

PR00722. CHYMOTRYPSIN.

SMART

SM00057. FIMAC. 1 hit.
SM00192. LDLa. 2 hits.
SM00202. SR. 1 hit.
SM00020. Tryp_SPc. 1 hit.
[Graphical view]

SUPFAM

SSF57424. LDL_rcpt_classA_cys-rich. 2 hits.
SSF50494. Pept_Ser_Cys. 1 hit.
SSF56487. Srcr_receptor. 1 hit.

PROSITE

PS51465. KAZAL_2. 1 hit.
PS01209. LDLRA_1. 1 hit.
PS50068. LDLRA_2. 2 hits.
PS00420. SRCR_1. False negative.
PS50287. SRCR_2. 1 hit.
PS50240. TRYPSIN_DOM. 1 hit.
PS00134. TRYPSIN_HIS. 1 hit.
PS00135. TRYPSIN_SER. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

NextBio

13512.

SOURCE

Search...

Entry information

Entry name

CFAI_HUMAN

Accession

Primary (citable) accession number: P05156
Secondary accession number(s): O60442

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 13, 1987
Last sequence update:	January 11, 2011
Last modified:	January 25, 2012
This is version 138 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.