Q9Y239 (NOD1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Nucleotide-binding oligomerization domain-containing protein 1

Alternative name(s):
Caspase recruitment domain-containing protein 4

Gene names

Name:	NOD1
Synonyms:	CARD4

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	953 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Enhances caspase-9-mediated apoptosis. Induces NF-kappa-B activity via RIPK2 and IKK-gamma. Confers responsiveness to intracellular bacterial lipopolysaccharides (LPS). Forms an intracellular sensing system along with ARHGEF2 for the detection of microbial effectors during cell invasion by pathogens. Required for RHOA and RIPK2 dependent NF-kappa-B signaling pathway activation upon S.flexneri cell invasion. Involved not only in sensing peptidoglycan (PGN)-derived muropeptides but also in the activation of NF-kappa-B by Shigella effector proteins IpgB2 and OspB. Recruits NLRP10 to the cell membrane following bacterial infection. Ref.5 Ref.7 Ref.8 Ref.11
Subunit structure	Homodimer. Self-associates. Binds to caspase-9 and RIPK2 by CARD-CARD interaction. Interacts with ARHGEF2. Interacts with NLRP10 and recruits it to the cell membrane following invasive bacterial infection. Ref.7 Ref.8 Ref.10 Ref.11 Ref.12
Subcellular location	Cytoplasm. Cell membrane. Apical cell membrane. Basolateral cell membrane. Note: Detected in the cytoplasm and at the cell membrane. Following bacterial infection, localizes to bacterial entry sites in the cell membrane. Recruited to the basolateral and apical membranes in polarized epithelial cells. Ref.6 Ref.7
Tissue specificity	Highly expressed in adult heart, skeletal muscle, pancreas, spleen and ovary. Also detected in placenta, lung, liver, kidney, thymus, testis, small intestine and colon.
Sequence similarities	Contains 1 CARD domain. Contains 9 LRR (leucine-rich) repeats. Contains 1 NACHT domain.

Ontologies

Keywords
Biological process	Apoptosis Immunity Innate immunity
Cellular component	Cell membrane Cytoplasm Membrane
Coding sequence diversity	Polymorphism
Domain	Leucine-rich repeat Repeat
Ligand	ATP-binding Nucleotide-binding
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	JNK cascade Traceable author statement. Source: Reactome MyD88-dependent toll-like receptor signaling pathway Traceable author statement. Source: Reactome TRIF-dependent toll-like receptor signaling pathway Traceable author statement. Source: Reactome activation of MAPK activity Traceable author statement. Source: Reactome defense response to Gram-positive bacterium Inferred from electronic annotation. Source: Compara defense response to bacterium Inferred from direct assay PubMed 15653568. Source: HGNC detection of bacterium Inferred from direct assay PubMed 15653568. Source: HGNC induction of apoptosis Inferred from direct assay Ref.2. Source: MGI inflammatory response Traceable author statement PubMed 15967716. Source: HGNC innate immune response Traceable author statement. Source: Reactome interleukin-8 biosynthetic process Inferred from direct assay PubMed 15653568. Source: HGNC nucleotide-binding oligomerization domain containing signaling pathway Traceable author statement. Source: Reactome positive regulation of ERK1 and ERK2 cascade Inferred from electronic annotation. Source: Compara positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from direct assay Ref.2. Source: MGI positive regulation of JNK cascade Inferred from electronic annotation. Source: Compara positive regulation of NF-kappaB transcription factor activity Inferred from direct assay Ref.11Ref.7. Source: UniProtKB positive regulation of dendritic cell antigen processing and presentation Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of interleukin-6 production Inferred from electronic annotation. Source: Compara positive regulation of tumor necrosis factor production Inferred from electronic annotation. Source: Compara protein oligomerization Traceable author statement PubMed 15967716. Source: HGNC toll-like receptor 10 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 2 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 3 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 4 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 5 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 9 signaling pathway Traceable author statement. Source: Reactome toll-like receptor TLR1:TLR2 signaling pathway Traceable author statement. Source: Reactome toll-like receptor TLR6:TLR2 signaling pathway Traceable author statement. Source: Reactome
Cellular_component	apical plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell basolateral plasma membrane Inferred from direct assay Ref.7. Source: UniProtKB cytosol Traceable author statement. Source: Reactome
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW CARD domain binding Inferred from direct assay Ref.2. Source: MGI cysteine-type endopeptidase activator activity involved in apoptotic process Traceable author statement Ref.2. Source: ProtInc identical protein binding Inferred from direct assay Ref.2. Source: MGI peptidoglycan binding Traceable author statement PubMed 15967716. Source: HGNC
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		2	EBI-1051262,EBI-1051262

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 953

953

Nucleotide-binding oligomerization domain-containing protein 1

PRO_0000144077

Regions

Domain

15 – 105

91

CARD

Domain

196 – 531

336

NACHT

Repeat

632 – 656

25

LRR 1

Repeat

702 – 725

24

LRR 2

Repeat

727 – 750

24

LRR 3

Repeat

755 – 778

24

LRR 4

Repeat

783 – 806

24

LRR 5

Repeat

839 – 862

24

LRR 6

Repeat

867 – 891

25

LRR 7

Repeat

895 – 918

24

LRR 8

Repeat

923 – 946

24

LRR 9

Nucleotide binding

202 – 209

8

ATP Potential

Natural variations

Natural variant

266

1

E → K.
Corresponds to variant rs2075820 [ dbSNP | Ensembl ].

VAR_020371

Natural variant

372

1

D → N.
Corresponds to variant rs5743342 [ dbSNP | Ensembl ].

VAR_053624

Natural variant

447

1

R → H. Ref.4
Corresponds to variant rs2975634 [ dbSNP | Ensembl ].

VAR_053625

Natural variant

605

1

R → W.
Corresponds to variant rs5743345 [ dbSNP | Ensembl ].

VAR_053626

Natural variant

610

1

A → T.
Corresponds to variant rs5743346 [ dbSNP | Ensembl ].

VAR_053627

Experimental info

Mutagenesis

41

1

V → A: Abolishes interaction with RIPK2/RICK. Ref.2 Ref.11

Mutagenesis

41

1

V → Q: Abolishes caspase-9 activation. Ref.2 Ref.11

Mutagenesis

44

1

L → A: Abolishes activation of NF-kappa-B. No effect on interaction with RIPK2. Ref.11

Mutagenesis

48

1

D → K: Abolishes activation of NF-kappa-B. No effect on interaction with RIPK2. Ref.11

Mutagenesis

53

1

E → K: No effect on activation of NF-kappa-B. Abolishes interaction with RIPK2. Ref.11

Mutagenesis

54

1

D → K: Abolishes activation of NF-kappa-B. Abolishes interaction with RIPK2. Ref.11

Mutagenesis

56

1

E → K: Abolishes activation of NF-kappa-B. Abolishes interaction with RIPK2. Ref.11

Mutagenesis

69

1

R → E: Abolishes activation of NF-kappa-B. Abolishes interaction with RIPK2. Ref.11

Mutagenesis

208

1

K → R: Reduces caspase-9 activation. Reduced binding affinity for NLRP10. Does not associate with cell membrane. Ref.2 Ref.6 Ref.8

Mutagenesis

287

1

D → A: Reduced binding affinity for NLRP10. Ref.8

Mutagenesis

711

1

D → S: Does not associate with cell membrane. Ref.6

Mutagenesis

788

1

H → S: No effect on association with cell membrane. Ref.6

Mutagenesis

792

1

G → S: Does not associate with cell membrane. Ref.6

Mutagenesis

877

1

Q → S: Does not associate with cell membrane. Ref.6

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

953

Helix Strand Turn

Details...

Helix

18 – 25

8

Helix

27 – 33

7

Helix

38 – 46

9

Helix

52 – 59

8

Beta strand

61 – 63

3

Helix

64 – 78

15

Helix

80 – 95

16

Helix

98 – 100

3

Helix

101 – 105

5

Sequences

	Sequence		Length	Mass (Da)
	Q9Y239 [UniParc]. Last modified November 1, 1999. Version 1. Checksum: 0A9DF5FC6487E21A	FASTA	953	107,691
	10 20 30 40 50 60 MEEQGHSEME IIPSESHPHI QLLKSNRELL VTHIRNTQCL VDNLLKNDYF SAEDAEIVCA 70 80 90 100 110 120 CPTQPDKVRK ILDLVQSKGE EVSEFFLYLL QQLADAYVDL RPWLLEIGFS PSLLTQSKVV 130 140 150 160 170 180 VNTDPVSRYT QQLRHHLGRD SKFVLCYAQK EELLLEEIYM DTIMELVGFS NESLGSLNSL 190 200 210 220 230 240 ACLLDHTTGI LNEQGETIFI LGDAGVGKSM LLQRLQSLWA TGRLDAGVKF FFHFRCRMFS 250 260 270 280 290 300 CFKESDRLCL QDLLFKHYCY PERDPEEVFA FLLRFPHVAL FTFDGLDELH SDLDLSRVPD 310 320 330 340 350 360 SSCPWEPAHP LVLLANLLSG KLLKGASKLL TARTGIEVPR QFLRKKVLLR GFSPSHLRAY 370 380 390 400 410 420 ARRMFPERAL QDRLLSQLEA NPNLCSLCSV PLFCWIIFRC FQHFRAAFEG SPQLPDCTMT 430 440 450 460 470 480 LTDVFLLVTE VHLNRMQPSS LVQRNTRSPV ETLHAGRDTL CSLGQVAHRG MEKSLFVFTQ 490 500 510 520 530 540 EEVQASGLQE RDMQLGFLRA LPELGPGGDQ QSYEFFHLTL QAFFTAFFLV LDDRVGTQEL 550 560 570 580 590 600 LRFFQEWMPP AGAATTSCYP PFLPFQCLQG SGPAREDLFK NKDHFQFTNL FLCGLLSKAK 610 620 630 640 650 660 QKLLRHLVPA AALRRKRKAL WAHLFSSLRG YLKSLPRVQV ESFNQVQAMP TFIWMLRCIY 670 680 690 700 710 720 ETQSQKVGQL AARGICANYL KLTYCNACSA DCSALSFVLH HFPKRLALDL DNNNLNDYGV 730 740 750 760 770 780 RELQPCFSRL TVLRLSVNQI TDGGVKVLSE ELTKYKIVTY LGLYNNQITD VGARYVTKIL 790 800 810 820 830 840 DECKGLTHLK LGKNKITSEG GKYLALAVKN SKSISEVGMW GNQVGDEGAK AFAEALRNHP 850 860 870 880 890 900 SLTTLSLASN GISTEGGKSL ARALQQNTSL EILWLTQNEL NDEVAESLAE MLKVNQTLKH 910 920 930 940 950 LWLIQNQITA KGTAQLADAL QSNTGITEIC LNGNLIKPEE AKVYEDEKRI ICF

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human CARD4 protein is a novel CED-4/Apaf-1 cell death family member that activates NF-kappaB." Bertin J., Nir W.-J., Fischer C.M., Tayber O.V., Errada P.R., Grant J.R., Keilty J.J., Gosselin M.L., Robison K.E., Wong G.H.W., Glucksmann M.A., DiStefano P.S. J. Biol. Chem. 274:12955-12958(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Endothelial cell.
[2]	"Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-kappaB." Inohara N., Koseki T., del Peso L., Hu Y., Yee C., Chen S., Carrio R., Merino J., Liu D., Ni J., Nunez G. J. Biol. Chem. 274:14560-14567(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], MUTAGENESIS OF VAL-41 AND LYS-208. Tissue: Mammary gland.
[3]	"The DNA sequence of human chromosome 7." Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., Delehaunty K.D., Miner T.L. , Nash W.E., Cordes M., Du H., Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., Wilson R.K. Nature 424:157-164(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT HIS-447. Tissue: Lymph.
[5]	"Human Nod1 confers responsiveness to bacterial lipopolysaccharides." Inohara N., Ogura Y., Chen F.F., Muto A., Nunez G. J. Biol. Chem. 276:2551-2554(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[6]	"The pattern-recognition molecule Nod1 is localized at the plasma membrane at sites of bacterial interaction." Kufer T.A., Kremmer E., Adam A.C., Philpott D.J., Sansonetti P.J. Cell. Microbiol. 10:477-486(2008) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-208; ASP-711; HIS-788; GLY-792 AND GLN-877.
[7]	"GEF-H1 mediated control of NOD1 dependent NF-kappaB activation by Shigella effectors." Fukazawa A., Alonso C., Kurachi K., Gupta S., Lesser C.F., McCormick B.A., Reinecker H.C. PLoS Pathog. 4:E1000228-E1000228(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH ARHGEF2.
[8]	"NLRP10 enhances Shigella-induced pro-inflammatory responses." Lautz K., Damm A., Menning M., Wenger J., Adam A.C., Zigrino P., Kremmer E., Kufer T.A. Cell. Microbiol. 14:1568-1583(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH NLRP10, MUTAGENESIS OF LYS-208 AND ASP-287.
[9]	"Solution structure of the CARD domain in human caspase recruitment domain protein 4 (NOD1 protein)." RIKEN structural genomics initiative (RSGI) Submitted (DEC-2006) to the PDB data bank Cited for: STRUCTURE BY NMR OF 14-110.
[10]	"Crystal structure of the Nod1 caspase activation and recruitment domain." Coussens N.P., Mowers J.C., McDonald C., Nunez G., Ramaswamy S. Biochem. Biophys. Res. Commun. 353:1-5(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 16-108, SUBUNIT.
[11]	"Solution structure of NOD1 CARD and mutational analysis of its interaction with the CARD of downstream kinase RICK." Manon F., Favier A., Nunez G., Simorre J.P., Cusack S. J. Mol. Biol. 365:160-174(2007) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 15-138, FUNCTION, INTERACTION WITH RIPK2, MUTAGENESIS OF VAL-41; LEU-44; ASP-48; GLU-53; ASP-54; GLU-56 AND ARG-69.
[12]	"Monomer/dimer transition of the caspase-recruitment domain of human Nod1." Srimathi T., Robbins S.L., Dubas R.L., Hasegawa M., Inohara N., Park Y.C. Biochemistry 47:1319-1325(2008) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 9-106, SUBUNIT.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF126484 mRNA. Translation: AAD29125.1.
AF149774 Genomic DNA. Translation: AAD43922.1.
AF113925 mRNA. Translation: AAD28350.1.
AC006027 Genomic DNA. Translation: AAS46897.1.
BC040339 mRNA. Translation: AAH40339.1.

IPI

IPI00005776.

RefSeq

NP_006083.1. NM_006092.2.

UniGene

Hs.405153.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2B1W	NMR	-	A	15-138	[»]
2DBD	NMR	-	A	17-110	[»]
2NSN	X-ray	2.00	A	16-108	[»]
2NZ7	X-ray	1.90	A/B	9-106	[»]
4E9M	X-ray	2.15	A/B/C/D/E/F	2-138	[»]

ProteinModelPortal

Q9Y239.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-41064N.

IntAct

Q9Y239. 3 interactions.

MINT

MINT-90728.

STRING

9606.ENSP00000222823.

PTM databases

PhosphoSite

Q9Y239.

Polymorphism databases

DMDM

20137579.

Proteomic databases

PaxDb

Q9Y239.

PRIDE

Q9Y239.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000222823; ENSP00000222823; ENSG00000106100.

GeneID

10392.

KEGG

hsa:10392.

UCSC

uc003tav.3. human.

Organism-specific databases

CTD

10392.

GeneCards

GC07M030464.

HGNC

HGNC:16390. NOD1.

MIM

605980. gene.

neXtProt

NX_Q9Y239.

PharmGKB

PA162398098.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG275503.

HOGENOM

HOG000113813.

HOVERGEN

HBG050793.

InParanoid

Q9Y239.

KO

K08727.

OMA

NDYGVRE.

OrthoDB

EOG4WH8K2.

PhylomeDB

Q9Y239.

Enzyme and pathway databases

Reactome

REACT_6782. TRAF6 Mediated Induction of proinflammatory cytokines.
REACT_6900. Immune System.

SignaLink

Q9Y239.

Gene expression databases

ArrayExpress

Q9Y239.

Bgee

Q9Y239.

CleanEx

HS_NOD1.

Genevestigator

Q9Y239.

GermOnline

ENSG00000106100. Homo sapiens.

Family and domain databases

Gene3D

1.10.533.10. 1 hit.

InterPro

IPR001315. CARD.
IPR011029. DEATH-like_dom.
IPR007111. NACHT_NTPase.
[Graphical view]

Pfam

PF00619. CARD. 1 hit.
[Graphical view]

SUPFAM

SSF47986. DEATH_like. 1 hit.

PROSITE

PS50209. CARD. 1 hit.
PS50837. NACHT. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

Q9Y239.

ChEMBL

CHEMBL1293222.

EvolutionaryTrace

Q9Y239.

GenomeRNAi

10392.

NextBio

39370.

SOURCE

Search...

Entry information

Entry name

NOD1_HUMAN

Accession

Primary (citable) accession number: Q9Y239
Secondary accession number(s): Q549U4, Q8IWF5

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 31, 2002
Last sequence update:	November 1, 1999
Last modified:	May 29, 2013
This is version 131 of the entry and version 1 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.