Reviewed, UniProtKB/Swiss-Prot Q9BYX4 (IFIH1_HUMAN)

Names and origin

Protein names

Recommended name:
    Interferon-induced helicase C domain-containing protein 1
    EC=3.6.1.-
Alternative name(s):
    Interferon-induced with helicase C domain protein 1
    Helicase with 2 CARD domains
      Short name=Helicard
    Melanoma differentiation-associated protein 5
      Short name=MDA-5
    RNA helicase-DEAD box protein 116
    Murabutide down-regulated protein

Gene names

Name:	IFIH1
Synonyms:	MDA5, RH116

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	1025 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	RNA helicase that, through its ATP-dependent unwinding of RNA, may function to promote message degradation by specific RNases. Seems to have growth suppressive properties. Involved in innate immune defense against viruses. Upon interaction with intracellular dsRNA produced during viral replication, triggers a transduction cascade involving MAVS/IPS1, which results in the activation of NF-kappa-B, IRF3 and IRF7 and the induction of the expression of antiviral cytokines such as IFN-beta and RANTES (CCL5). ATPase activity is specifically induced by dsRNA. Essential for the production of interferons in response to picornaviruses. Ref.2
Subunit structure	Interacts with MAVS. Interacts with V protein of Simian virus 5, Human parainfluenza virus 2, Mumps virus, Sendai virus and Hendra virus. Binding to paramyxoviruses V proteins prevents IFN-beta induction, and the further establishment of an antiviral state. Ref.7 Ref.8 Ref.9
Subcellular location	Cytoplasm. Nucleus Potential. Note: May be found in the nucleus, during apoptosis.
Tissue specificity	Widely expressed, at a low level. Expression is detected at slightly highest levels in placenta, pancreas and spleen and at barely levels in detectable brain, testis and lung. Ref.2 Ref.1 Ref.5
Induction	By IFN-beta and TNF-alpha. Ref.1
Post-translational modification	During apoptosis, processed into 3 cleavage products. The helicase-containing fragment, once liberated from the CARD domains, translocate from the cytoplasm to the nucleus. The processed protein significantly sensitizes cells to DNA degradation By similarity.
Involvement in disease	Genetic variation in IFIH1 is associated with insulin-dependent diabetes mellitus 19 (IDDM19) [MIM:610155].
Miscellaneous	In HIV-1 infected HeLa-CD4 cells, overexpression of IFIH1 results in a great increase in the level of secreted viral p24 protein.
Sequence similarities	Belongs to the helicase family. Contains 2 CARD domains. Contains 1 helicase ATP-binding domain. Contains 1 helicase C-terminal domain.
Sequence caution	The sequence AAH78180.1 differs from that shown. Reason: Miscellaneous discrepancy. Contaminating sequence. Potential poly-A sequence.

Ontologies

Keywords
Biological process	Antiviral defense Host-virus interaction Immune response Innate immunity
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Diabetes mellitus
Domain	Repeat
Ligand	ATP-binding Nucleotide-binding RNA-binding
Molecular function	Helicase Hydrolase
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	innate immune response Inferred from electronic annotation. Source: UniProtKB-KW interspecies interaction between organisms Inferred from electronic annotation. Source: UniProtKB-KW regulation of apoptosis Inferred from electronic annotation. Source: InterPro response to virus Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytoplasm Inferred from direct assay. Source: HPA nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW DNA binding Inferred from electronic annotation. Source: InterPro RNA binding Inferred from electronic annotation. Source: UniProtKB-KW helicase activity Inferred from electronic annotation. Source: UniProtKB-KW protein binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q9BYX4-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q9BYX4-2)

The sequence of this isoform differs from the canonical sequence as follows:
     208-221: EIENLSQVDGPQVE → GICNFTEEDSSNSA
     222-1025: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 1025

1025

Interferon-induced helicase C domain-containing protein 1

PRO_0000102012

Regions

Domain

7 – 97

91

CARD 1

Domain

110 – 190

81

CARD 2

Domain

316 – 509

194

Helicase ATP-binding

Domain

700 – 882

183

Helicase C-terminal

Sites

Site

208 – 209

2

Cleavage By similarity

Site

216 – 217

2

Cleavage By similarity

Site

251 – 252

2

Cleavage By similarity

Amino acid modifications

Modified residue

289

1

Phosphoserine By similarity

Modified residue

301

1

Phosphoserine By similarity

Modified residue

645

1

Phosphoserine By similarity

Natural variations

Alternative sequence

208 – 221

14

EIENL…GPQVE → GICNFTEEDSSNSA in isoform 2.

VSP_013337

Alternative sequence

222 – 1025

804

Missing in isoform 2.

VSP_013338

Natural variant

460

1

H → R: dbSNP rs10930046.

VAR_031226

Natural variant

843

1

H → R: dbSNP rs3747517. Ref.2 Ref.3 Ref.4

VAR_021594

Natural variant

946

1

A → T Associated with susceptibility to insulin-dependent diabetes mellitus. dbSNP rs1990760. Ref.3 Ref.4 Ref.11

VAR_021595

Experimental info

Mutagenesis

251

1

D → A: No cleavage and no acceleration of DNA degradation. Ref.5

Mutagenesis

444

1

E → A: No acceleration of DNA degradation, no binding to ATP, and no helicase activity. Ref.5

Sequence conflict

439

1

L → F in AAG54076. Ref.2

Sequence conflict

475

1

N → H in BAB71141. Ref.4

Sequence conflict

592

1

E → K in AAG34368. Ref.1

Sequence conflict

598

1

R → S in AAG54076. Ref.2

Sequence conflict

609

1

E → K in AAG54076. Ref.2

Sequence conflict

782

1

K → R in BAB71141. Ref.4

Secondary structure

1

.

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.

.

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1025

Helix Strand Turn

Details...

Helix

293 – 299

7

Helix

310 – 320

11

Beta strand

325 – 328

4

Helix

332 – 352

21

Beta strand

359 – 365

7

Helix

366 – 375

10

Helix

377 – 381

5

Turn

382 – 384

3

Beta strand

387 – 389

3

Helix

400 – 406

7

Beta strand

408 – 413

6

Helix

414 – 422

9

Helix

434 – 436

3

Beta strand

438 – 442

5

Helix

454 – 473

20

Beta strand

483 – 488

6

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified March 20, 2007. Version 3. Checksum: 789CFB4824B92DC9	FASTA	1,025	116,689
	10 20 30 40 50 60 MSNGYSTDEN FRYLISCFRA RVKMYIQVEP VLDYLTFLPA EVKEQIQRTV ATSGNMQAVE 70 80 90 100 110 120 LLLSTLEKGV WHLGWTREFV EALRRTGSPL AARYMNPELT DLPSPSFENA HDEYLQLLNL 130 140 150 160 170 180 LQPTLVDKLL VRDVLDKCME EELLTIEDRN RIAAAENNGN ESGVRELLKR IVQKENWFSA 190 200 210 220 230 240 FLNVLRQTGN NELVQELTGS DCSESNAEIE NLSQVDGPQV EEQLLSTTVQ PNLEKEVWGM 250 260 270 280 290 300 ENNSSESSFA DSSVVSESDT SLAEGSVSCL DESLGHNSNM GSDSGTMGSD SDEENVAARA 310 320 330 340 350 360 SPEPELQLRP YQMEVAQPAL EGKNIIICLP TGSGKTRVAV YIAKDHLDKK KKASEPGKVI 370 380 390 400 410 420 VLVNKVLLVE QLFRKEFQPF LKKWYRVIGL SGDTQLKISF PEVVKSCDII ISTAQILENS 430 440 450 460 470 480 LLNLENGEDA GVQLSDFSLI IIDECHHTNK EAVYNNIMRH YLMQKLKNNR LKKENKPVIP 490 500 510 520 530 540 LPQILGLTAS PGVGGATKQA KAEEHILKLC ANLDAFTIKT VKENLDQLKN QIQEPCKKFA 550 560 570 580 590 600 IADATREDPF KEKLLEIMTR IQTYCQMSPM SDFGTQPYEQ WAIQMEKKAA KEGNRKERVC 610 620 630 640 650 660 AEHLRKYNEA LQINDTIRMI DAYTHLETFY NEEKDKKFAV IEDDSDEGGD DEYCDGDEDE 670 680 690 700 710 720 DDLKKPLKLD ETDRFLMTLF FENNKMLKRL AENPEYENEK LTKLRNTIME QYTRTEESAR 730 740 750 760 770 780 GIIFTKTRQS AYALSQWITE NEKFAEVGVK AHHLIGAGHS SEFKPMTQNE QKEVISKFRT 790 800 810 820 830 840 GKINLLIATT VAEEGLDIKE CNIVIRYGLV TNEIAMVQAR GRARADESTY VLVAHSGSGV 850 860 870 880 890 900 IEHETVNDFR EKMMYKAIHC VQNMKPEEYA HKILELQMQS IMEKKMKTKR NIAKHYKNNP 910 920 930 940 950 960 SLITFLCKNC SVLACSGEDI HVIEKMHHVN MTPEFKELYI VRENKALQKK CADYQINGEI 970 980 990 1000 1010 1020 ICKCGQAWGT MMVHKGLDLP CLKIRNFVVV FKNNSTKKQY KKWVELPITF PNLDYSECCL FSDED
	Isoform 2. Checksum: 3C7139ECAC564BB5	FASTA	221	25,129
	10 20 30 40 50 60 MSNGYSTDEN FRYLISCFRA RVKMYIQVEP VLDYLTFLPA EVKEQIQRTV ATSGNMQAVE 70 80 90 100 110 120 LLLSTLEKGV WHLGWTREFV EALRRTGSPL AARYMNPELT DLPSPSFENA HDEYLQLLNL 130 140 150 160 170 180 LQPTLVDKLL VRDVLDKCME EELLTIEDRN RIAAAENNGN ESGVRELLKR IVQKENWFSA 190 200 210 220 FLNVLRQTGN NELVQELTGS DCSESNAGIC NFTEEDSSNS A

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"mda-5: an interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties." Kang D.-C., Gopalkrishnan R.V., Wu Q., Jankowsky E., Pyle A.M., Fisher P.B. Proc. Natl. Acad. Sci. U.S.A. 99:637-642(2002) [PubMed: 11805321] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INDUCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY. Tissue: Melanoma.
[2]	"A novel cellular RNA helicase, RH116, differentially regulates cell growth, programmed cell death and human immunodeficiency virus type 1 replication." Cocude C., Truong M.-J., Billaut-Mulot O., Delsart V., Darcissac E., Capron A., Mouton Y., Bahr G.M. J. Gen. Virol. 84:3215-3225(2003) [PubMed: 14645903] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, VARIANT ARG-843. Tissue: Spleen.
[3]	"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] (ISOFORMS 1 AND 2), VARIANTS ARG-843 AND THR-946. Tissue: Uterus.
[4]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 475-1025 (ISOFORM 1), VARIANTS ARG-843 AND THR-946.
[5]	"Overexpression of Helicard, a CARD-containing helicase cleaved during apoptosis, accelerates DNA degradation." Kovacsovics M., Martinon F., Micheau O., Bodmer J.-L., Hofmann K., Tschopp J. Curr. Biol. 12:838-843(2002) [PubMed: 12015121] [Abstract] Cited for: MUTAGENESIS OF ASP-251 AND GLU-444, TISSUE SPECIFICITY.
[6]	Erratum Kovacsovics M., Martinon F., Micheau O., Bodmer J.-L., Hofmann K., Tschopp J. Curr. Biol. 12:1633-1633(2002)
[7]	"The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter." Andrejeva J., Childs K.S., Young D.F., Carlos T.S., Stock N., Goodbourn S., Randall R.E. Proc. Natl. Acad. Sci. U.S.A. 101:17264-17269(2004) [PubMed: 15563593] [Abstract] Cited for: INTERACTION WITH PARAMYXOVIRUSES V PROTEIN.
[8]	"IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction." Kawai T., Takahashi K., Sato S., Coban C., Kumar H., Kato H., Ishii K.J., Takeuchi O., Akira S. Nat. Immunol. 6:981-988(2005) [PubMed: 16127453] [Abstract] Cited for: INTERACTION WITH MAVS.
[9]	"Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus." Meylan E., Curran J., Hofmann K., Moradpour D., Binder M., Bartenschlager R., Tschopp J. Nature 437:1167-1172(2005) [PubMed: 16177806] [Abstract] Cited for: INTERACTION WITH MAVS.
[10]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[11]	"A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region." Smyth D.J., Cooper J.D., Bailey R., Field S., Burren O., Smink L.J., Guja C., Ionescu-Tirgoviste C., Widmer B., Dunger D.B., Savage D.A., Walker N.M., Clayton D.G., Todd J.A. Nat. Genet. 38:617-619(2006) [PubMed: 16699517] [Abstract] Cited for: VARIANT THR-946, ASSOCIATION WITH INSULIN-DEPENDENT DIABETES MELLITUS 19.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

AF095844 mRNA. Translation: AAG34368.1.
AY017378 mRNA. Translation: AAG54076.1.
BC046208 mRNA. Translation: AAH46208.1.
BC078180 mRNA. Translation: AAH78180.1. Sequence problems.
BC111750 mRNA. Translation: AAI11751.1.
AK056293 mRNA. Translation: BAB71141.1. Different initiation.

IPI

IPI00005577.
IPI00556546.

RefSeq

NP_071451.2.

UniGene

Hs.163173

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2RQB	NMR	-	A	896-1025	[»]
3B6E	X-ray	1.60	A	277-490	[»]
3GA3	X-ray	1.45	A	893-1017	[»]

ModBase

Search...

PTM databases

PhosphoSite

Q9BYX4.

Genome annotation databases

Ensembl

ENSG00000115267. Homo sapiens. [Contig view]

GeneID

64135.

KEGG

hsa:64135.

Organism-specific databases

GeneCards

GC02M162831.

H-InvDB

HIX0002549.

HGNC

HGNC:18873. IFIH1.

HPA

HPA002656.

MIM

606951. gene.
610155. phenotype.

PharmGKB

PA134889215.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

Q9BYX4.

HOVERGEN

Q9BYX4.

OMA

Q9BYX4. ENEKFAE.

Gene expression databases

ArrayExpress

Q9BYX4.

Bgee

Q9BYX4.

CleanEx

HS_IFIH1.

GermOnline

ENSG00000115267. Homo sapiens.

Family and domain databases

InterPro

IPR001315. CARD.
IPR014001. DEAD-like_N.
IPR001650. DNA/RNA_helicase_C.
IPR014021. Helicase_SF1/SF2_ATP-bd.
IPR006935. Restrct_endonuc_I_R/III_Res.
[Graphical view]

Pfam

PF00619. CARD. 1 hit.
PF00271. Helicase_C. 1 hit.
PF04851. ResIII. 1 hit.
[Graphical view]

SMART

SM00487. DEXDc. 1 hit.
SM00490. HELICc. 1 hit.
[Graphical view]

PROSITE

PS50209. CARD. False negative.
PS51192. HELICASE_ATP_BIND_1. 1 hit.
PS51194. HELICASE_CTER. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

66034.

SOURCE

Search...

Entry information

Entry name

IFIH1_HUMAN

Accession

Primary (citable) accession number: Q9BYX4
Secondary accession number(s): Q2NKL6 , Q6DC96, Q86X56, Q96MX8, Q9H3G6

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 12, 2005
Last sequence update:	March 20, 2007
Last modified:	June 16, 2009
This is version 70 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)