O88522 (NEMO_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
NF-kappa-B essential modulator
Short name=NEMO

Alternative name(s):
IkB kinase-associated protein 1
Short name=IKKAP1
Short name=mFIP-3
Inhibitor of nuclear factor kappa-B kinase subunit gamma
Short name=I-kappa-B kinase subunit gamma
Short name=IKK-gamma
Short name=IKKG
Short name=IkB kinase subunit gamma
NF-kappa-B essential modifier

Gene names

Name:	Ikbkg
Synonyms:	Nemo

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	412 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Regulatory subunit of the IKK core complex which phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor. Also considered to be a mediator for TAX activation of NF-kappa-B. Could be implicated in NF-kappa-B-mediated protection from cytokine toxicity By similarity. Ref.8
Subunit structure	Homodimer; disulfide-linked. Component of the I-kappa-B-kinase (IKK) core complex consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK-beta/IKBKB dimers are associated with four gamma/IKBKG subunits. The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex. The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65. Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP. Interacts with COPS3, CYLD, NALP2, TRPC4AP and LRDD. Interacts with ATM; the complex is exported from the nucleus. Interacts with TRAF6. Interacts with TANK; the interaction is enhanced by TBK1 and IKBKE. Part of a ternary complex consisting of TANK, IKBKB and IKBKG. Interacts with ZFAND5. Interacts with RIPK2 By similarity. Ref.11 Ref.13
Subcellular location	Cytoplasm By similarity. Nucleus By similarity.
Domain	The leucine-zipper domain and the C2HC-type zinc-finger are essential for polyubiquitin binding and for the activation of IRF3 By similarity.
Post-translational modification	Phosphorylation at Ser-68 attenuates aminoterminal homodimerization By similarity. Polyubiquitinated on Lys-278 through 'Lys-63'; the ubiquitination is mediated by NOD2 and RIPK2 and probably plays a role in signaling by facilitating interactions with ubiquitin domain-containing proteins and activates the NF-kappa-B pathway.Polyubiquitinated on Lys-392 through 'Lys-63'; the ubiquitination is mediated by BCL10, MALT1 and TRAF6 and probably plays a role in signaling by facilitating interactions with ubiquitin domain-containing proteins and activates the NF-kappa-B pathway. Monoubiquitinated on Lys-270 and Lys-302; promotes nuclear export. Linear polyubiquitinated on Lys-111, Lys-143, Lys-226, Lys-246, Lys-270, Lys-278, Lys-285, Lys-295, Lys-302 and Lys-319; the head-to-tail polyubiquitination is mediated by the LUBAC complex and plays a key role in NF-kappa-B activation By similarity. Sumoylated on Lys-270 and Lys-302 by SUMO1; the modification results in phosphorylation of Ser-85 by ATM leading to a replacement of the sumoylation by mono-ubiquitination on these residues By similarity.
Sequence similarities	Contains 1 C2HC-type zinc finger.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Domain	Coiled coil Zinc-finger
Ligand	Metal-binding Zinc
PTM	Disulfide bond Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	B cell homeostasis Inferred from mutant phenotype. Source: MGI activation of NF-kappaB-inducing kinase activity Inferred from direct assay. Source: MGI transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Chuk	Q60680	3	EBI-998011,EBI-646245

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 412

412

NF-kappa-B essential modulator

PRO_0000096783

Regions

Domain

315 – 336

22

Leucine-zipper Potential

Zinc finger

389 – 410

22

C2HC-type

Region

44 – 111

68

Interaction with CHUK/IKBKB By similarity

Region

150 – 250

101

Interaction with TANK

Region

246 – 358

113

Self-association By similarity

Region

375 – 412

38

Interaction with CYLD By similarity

Coiled coil

49 – 345

297

Potential

Amino acid modifications

Modified residue

31

1

Phosphoserine; by IKKB By similarity

Modified residue

43

1

Phosphoserine; by IKKB By similarity

Modified residue

68

1

Phosphoserine By similarity

Modified residue

85

1

Phosphoserine; by ATM By similarity

Modified residue

369

1

Phosphoserine; by IKKB Ref.10

Modified residue

380

1

Phosphoserine By similarity

Disulfide bond

54

Interchain By similarity

Disulfide bond

340

Interchain By similarity

Cross-link

111

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Cross-link

139

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Cross-link

143

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Cross-link

226

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Cross-link

246

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Cross-link

270

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO); alternate By similarity

Cross-link

270

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternate By similarity

Cross-link

276

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Cross-link

278

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.12

Cross-link

285

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Cross-link

295

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Cross-link

302

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) By similarity

Cross-link

302

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternate By similarity

Cross-link

314

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.12

Cross-link

318

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.12

Cross-link

319

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.12

Cross-link

392

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.12

Experimental info

Mutagenesis

278

1

K → R: Slight decrease in TRAF6-induced polyubiquitination. Ref.12

Mutagenesis

314

1

K → R: Slight decrease in TRAF6-induced polyubiquitination. Important decrease in TRAF6-induced polyubiquitination; when associated with R-318 and R-319. Ref.12

Mutagenesis

316

1

V → P: Loss of interaction with TRAF6 and TRAF6-induced polyubiquitination. Ref.12

Mutagenesis

318

1

K → R: Slight decrease in TRAF6-induced polyubiquitination. Decrease in TRAF6-induced polyubiquitination; when associated with R-319. Important decrease in TRAF6-induced polyubiquitination; when associated with R-314 and R-319. Ref.12

Mutagenesis

319

1

K → R: Slight decrease in TRAF6-induced polyubiquitination. Decrease in TRAF6-induced polyubiquitination; when associated with R-318. Important decrease in TRAF6-induced polyubiquitination; when associated with R-314 and R-318. Ref.12

Mutagenesis

369

1

S → A: Decreases phosphorylation and increases NF-kappa-B activity. Ref.10

Mutagenesis

375

1

S → A: Decreases phosphorylation and increases NF-kappa-B activity. Ref.10

Mutagenesis

392

1

K → R: 40% decrease in IL1-induced NF-kappa-B activation. Ref.12

Sequence conflict

13

1

M → T in AAC40153. Ref.1

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

412

Helix Strand Turn

Details...

Helix

260 – 278

19

Helix

280 – 287

8

Helix

290 – 321

32

Helix

323 – 328

6

Helix

330 – 333

4

Sequences

	Sequence		Length	Mass (Da)
	O88522 [UniParc]. Last modified July 27, 2011. Version 2. Checksum: 66C693C857A2D5E6	FASTA	412	47,972
	10 20 30 40 50 60 MNKHPWKNQL SEMVQPSGGP AEDQDMLGEE SSLGKPAMLH LPSEQGTPET LQRCLEENQE 70 80 90 100 110 120 LRDAIRQSNQ MLRERCEELL HFQVSQREEK EFLMCKFQEA RKLVERLSLE KLDLRSQREQ 130 140 150 160 170 180 ALKELEQLKK CQQQMAEDKA SVKAQVTSLL GELQESQSRL EAATKDRQAL EGRIRAVSEQ 190 200 210 220 230 240 VRQLESEREV LQQQHSVQVD QLRMQNQSVE AALRMERQAA SEEKRKLAQL QAAYHQLFQD 250 260 270 280 290 300 YDSHIKSSKG MQLEDLRQQL QQAEEALVAK QELIDKLKEE AEQHKIVMET VPVLKAQADI 310 320 330 340 350 360 YKADFQAERH AREKLVEKKE YLQEQLEQLQ REFNKLKVGC HESARIEDMR KRHVETPQPP 370 380 390 400 410 LLPAPAHHSF HLALSNQRRS PPEEPPDFCC PKCQYQAPDM DTLQIHVMEC IE

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Complementation cloning of NEMO, a component of the I-kappaB kinase complex essential for NF-kappaB activation." Yamaoka S., Courtois G., Bessia C., Whiteside S.T., Weil R., Agou F., Kirk H.E., Kay R.J., Israel A. Cell 93:1231-1240(1998) [PubMed: 9657155] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: T-cell.
[2]	"Human-mouse comparative sequence analysis of the NEMO gene reveals an alternative promoter within the neighboring G6PD gene." Galgoczy P., Rosenthal A., Platzer M. Gene 271:93-98(2001) [PubMed: 11410370] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"Ikbkg gene modulates the herpes virus susceptibility in mice." Perelygin A.A., Perelygina L.M. Submitted (MAY-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: BALB/c. Tissue: Liver.
[4]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed: 16141072] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: NOD.
[5]	"Lineage-specific biology revealed by a finished genome assembly of the mouse." Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P. PLoS Biol. 7:E1000112-E1000112(2009) [PubMed: 19468303] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Strain: C57BL/6.
[6]	Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"IkappaB kinase (IKK)-associated protein 1, a common component of the heterogeneous IKK complex." Mercurio F., Murray B.W., Shevchenko A., Bennett B.L., Young D.B., Li J.W., Pascual G., Motiwala A., Zhu H., Mann M., Manning A.M. Mol. Cell. Biol. 19:1526-1538(1999) [PubMed: 9891086] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 85-412, PROTEIN SEQUENCE OF 144-159. Tissue: Cervix carcinoma.
[8]	"Identification of a cell protein (FIP-3) as a modulator of NF-kappaB activity and as a target of an adenovirus inhibitor of tumor necrosis factor alpha-induced apoptosis." Li Y., Kang J., Friedman J., Tarassishin L., Ye J., Kovalenko A., Wallach D., Horwitz M.S. Proc. Natl. Acad. Sci. U.S.A. 96:1042-1047(1999) [PubMed: 9927690] [Abstract] Cited for: FUNCTION.
[9]	"Role of ikkgamma/nemo in assembly of the IkappaB kinase complex." Li X.-H., Fang X., Gaynor R.B. J. Biol. Chem. 276:4494-4500(2001) [PubMed: 11080499] [Abstract] Cited for: IKK COMPLEX.
[10]	"Regulation of Ikappa B kinase (IKK)gamma /NEMO function by IKKbeta -mediated phosphorylation." Prajapati S., Gaynor R.B. J. Biol. Chem. 277:24331-24339(2002) [PubMed: 11971901] [Abstract] Cited for: PHOSPHORYLATION AT SER-369, MUTAGENESIS OF SER-369 AND SER-375.
[11]	"Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinases." Chariot A., Leonardi A., Muller J., Bonif M., Brown K., Siebenlist U. J. Biol. Chem. 277:37029-37036(2002) [PubMed: 12133833] [Abstract] Cited for: INTERACTION WITH TANK AND IKBKB.
[12]	"Identification of TRAF6-dependent NEMO polyubiquitination sites through analysis of a new NEMO mutation causing incontinentia pigmenti." Sebban-Benin H., Pescatore A., Fusco F., Pascuale V., Gautheron J., Yamaoka S., Moncla A., Ursini M.V., Courtois G. Hum. Mol. Genet. 16:2805-2815(2007) [PubMed: 17728323] [Abstract] Cited for: UBIQUITINATION AT LYS-278; LYS-314; LYS-318; LYS-319 AND LYS-392, MUTAGENESIS OF LYS-278; LYS-314; VAL-316; LYS-318; LYS-319 AND LYS-392.
[13]	"Telomere-independent Rap1 is an IKK adaptor and regulates NF-kappaB-dependent gene expression." Teo H., Ghosh S., Luesch H., Ghosh A., Wong E.T., Malik N., Orth A., de Jesus P., Perry A.S., Oliver J.D., Tran N.L., Speiser L.J., Wong M., Saez E., Schultz P., Chanda S.K., Verma I.M., Tergaonkar V. Nat. Cell Biol. 12:758-767(2010) [PubMed: 20622870] [Abstract] Cited for: INTERACTION WITH TERF2IP.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF069542 mRNA. Translation: AAC40153.1.
AF326207 Genomic DNA. Translation: AAK69186.1.
AF513109 mRNA. Translation: AAP47160.1.
AK154095 mRNA. Translation: BAE32372.1.
AL669976 Genomic DNA. Translation: CAM45971.1.
CH466650 Genomic DNA. Translation: EDL29810.1.

IPI

IPI00914699.

RefSeq

NP_001154895.1. NM_001161423.1.
NP_034677.2. NM_010547.2.

UniGene

Mm.12967.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2V4H	X-ray	2.90	A/B	251-337	[»]
2ZVN	X-ray	3.00	B/D/F/H	253-337	[»]
2ZVO	X-ray	2.90	B/D	250-339	[»]
3F89	X-ray	2.80	A/B	250-339	[»]
3JSV	X-ray	2.70	C/D	250-343	[»]

ProteinModelPortal

O88522.

SMR

O88522. Positions 49-109, 193-248, 256-341, 387-412.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29811N.

IntAct

O88522. 2 interactions.

MINT

MINT-143245.

STRING

O88522.

PTM databases

PhosphoSite

O88522.

Proteomic databases

PRIDE

O88522.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSMUST00000114127; ENSMUSP00000109762; ENSMUSG00000004221.
ENSMUST00000114128; ENSMUSP00000109763; ENSMUSG00000004221.
ENSMUST00000114133; ENSMUSP00000109768; ENSMUSG00000004221.
ENSMUST00000164101; ENSMUSP00000126770; ENSMUSG00000004221.

GeneID

16151.

KEGG

mmu:16151.

Organism-specific databases

CTD

8517.

MGI

MGI:1338074. Ikbkg.

Phylogenomic databases

HOVERGEN

HBG000417.

InParanoid

O88522.

OrthoDB

EOG42BX8V.

Gene expression databases

ArrayExpress

O88522.

Bgee

O88522.

CleanEx

MM_IKBKG.

Genevestigator

O88522.

GermOnline

ENSMUSG00000004221. Mus musculus.

Family and domain databases

InterPro

IPR021063. NEMO_N.
[Graphical view]

KO

K07210.

Pfam

PF11577. NEMO. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

NextBio

288945.

SOURCE

Search...

Entry information

Entry name

NEMO_MOUSE

Accession

Primary (citable) accession number: O88522
Secondary accession number(s): Q924H4

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	July 27, 2011
Last modified:	December 14, 2011
This is version 99 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program