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Protein

Nucleolar protein 3

Gene

Nol3

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Apoptosis repressor that blocks multiple modes of cell death. Inhibits extrinsic apoptotic pathways through two different ways. Firstly by interacting with FAS and FADD upon FAS activation blocking death-inducing signaling complex (DISC) assembly (PubMed:15383280). Secondly by interacting with CASP8 in a mitochondria localization- and phosphorylation-dependent manner, limiting the amount of soluble CASP8 available for DISC-mediated activation (PubMed:12191471). Inhibits intrinsic apoptotic pathway in response to a wide range of stresses, through its interaction with BAX resulting in BAX inactivation, preventing mitochondrial dysfunction and release of pro-apoptotic factors (PubMed:15383280). Inhibits calcium-mediated cell death by functioning as a cytosolic calcium buffer, dissociating its interaction with CASP8 and maintaining calcium homeostasis (PubMed:23382383). Negatively regulates oxidative stress-induced apoptosis by phosphorylation-dependent suppression of the mitochondria-mediated intrinsic pathway, by blocking CASP2 activation and BAX translocation (PubMed:16639714). Negatively regulates hypoxia-induced apoptosis in part by inhibiting the release of cytochrome c from mitochondria in a caspase-independent manner (PubMed:10590251). Also inhibits TNF-induced necrosis by preventing TNF-signaling pathway through TNFRSF1A interaction abrogating the recruitment of RIPK1 to complex I (By similarity). Finally through its role as apoptosis repressor, promotes vascular remodeling through inhibition of apoptosis and stimulation of proliferation, in response to hypoxia (By similarity). Inhibits too myoblast differentiation through caspase inhibition (PubMed:17292893).By similarity6 Publications

GO - Molecular functioni

  • caspase binding Source: UniProtKB
  • death effector domain binding Source: UniProtKB
  • kinase binding Source: UniProtKB
  • metal ion binding Source: UniProtKB-KW
  • phosphatase binding Source: UniProtKB

GO - Biological processi

  • cellular response to hypoxia Source: UniProtKB
  • inhibition of cysteine-type endopeptidase activity Source: UniProtKB
  • mRNA splice site selection Source: UniProtKB
  • myoblast differentiation Source: UniProtKB
  • negative regulation of apoptotic process Source: UniProtKB
  • negative regulation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
  • negative regulation of cytosolic calcium ion concentration Source: UniProtKB
  • negative regulation of death-inducing signaling complex assembly Source: UniProtKB
  • negative regulation of extrinsic apoptotic signaling pathway via death domain receptors Source: UniProtKB
  • negative regulation of hydrogen peroxide-induced cell death Source: UniProtKB
  • negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway Source: UniProtKB
  • negative regulation of intrinsic apoptotic signaling pathway Source: UniProtKB
  • negative regulation of mitochondrial calcium ion concentration Source: UniProtKB
  • negative regulation of protein targeting to mitochondrion Source: UniProtKB
  • negative regulation of release of cytochrome c from mitochondria Source: UniProtKB
  • protein complex oligomerization Source: UniProtKB
  • regulation of apoptotic process Source: RGD
  • regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum Source: UniProtKB
  • response to hypoxia Source: RGD
  • smooth muscle cell proliferation Source: UniProtKB

Keywordsi

Biological processmRNA processing
LigandCalcium, Metal-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Nucleolar protein 3
Alternative name(s):
Apoptosis repressor with CARD
Gene namesi
Name:Nol3
Synonyms:Arc
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi708558 Nol3

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Membrane, Mitochondrion, Sarcoplasmic reticulum

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi31L → F: Failed to protect against extrinsic and intrinsic apoptotic pathways; when associated with R-69. Not interferes with death-inducing signaling complex (DISC) assembly; when associated with R-69. Promotes BAX activation; when associated with R-69. 1 Publication1
Mutagenesisi69G → R: Failed to protect against extrinsic and intrinsic apoptotic pathways; when associated with F-31. Not interferes with DISC assembly; when associated with F-31. Promotes BAX activation; when associated with F-31. 1 Publication1
Mutagenesisi149T → A: Not phosphorylated by CK2. Loses the ability to block CASP8-, FAS-, or TNFRSF1A-induced apoptosis. Prevents translocation to mitochondria. Significantly decreases resistance to hydrogen peroxide-induced cell death. Doesn't interact with PPM1G, BAX and CASP2. Doesn't inhibit CASP2 and CASP3 activation. Doesn't was inhibit CASP8-induced apoptosis. 3 Publications1
Mutagenesisi149T → D: Significantly enhances resistance against hydrogen peroxide- and induced by isoproterenol or aldosterone-induced cell death. 2 Publications1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00001441012 – 221Nucleolar protein 3Add BLAST220

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Lipidationi2N-myristoyl glycineBy similarity1
Modified residuei149Phosphothreonine; by CK2Combined sources1 Publication1

Post-translational modificationi

Phosphorylation at Thr-149 is required for its antiapoptotic effect by blocking death-inducing signaling complex (DISC) activity through the control of interaction with CASP8. Phosphorylation at Thr-149 results in translocation to mitochondria and this translocation enables the binding to CASP8 (PubMed:12191471). Dephosphorylated at Thr-149 by calcineurin; doesn't inhibit the association between FADD and CASP8 and the consequent apoptosis (PubMed:19001025).2 Publications
Polyubiquitinated by MDM2; promoting proteasomal-dependent degradation in response to apoptotic stimuli.By similarity1 Publication

Keywords - PTMi

Lipoprotein, Myristate, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ62881
PRIDEiQ62881

PTM databases

iPTMnetiQ62881
PhosphoSitePlusiQ62881
SwissPalmiQ62881

Expressioni

Tissue specificityi

Highly expressed in skeletal muscle, heart and medulla.1 Publication

Inductioni

Increased by chronic hypoxia (PubMed:22082675). Activated by FOXO3 (PubMed:23382383). Negatively regulated by TP53 (PubMed:17998337).3 Publications

Interactioni

Subunit structurei

Oligomerizes (via CARD doamin) (By similarity). Interacts (via CARD domain) with CASP2; inhibits CASP2 activity in a phosphorylation-dependent manner. Interacts with CASP8; decreases CASP8 activity in a mitochondria localization- and phosphorylation-dependent manner and this interaction is dissociated by calcium. Interacts with TFPT; translocates NOL3 into the nucleus and negatively regulated TFPT-induced cell death. Interacts directly (via CARD domain) with FAS and FADD (via DED domain); inhibits death-inducing signaling complex (DISC) assembly by inhibiting the increase in FAS-FADD binding induced by FAS activation. Interacts (via CARD domain) with BAX (via a C-terminal 33 residues); inhibits BAX activation and translocation and consequently cytochrome c release from mitochondria. Interacts with PPM1G; may dephosphorylate NOL3. Interacts (via CARD domain) with BBC3 (via BH3 domain); preventing the association of BBC3 with BCL2 and resulting in activation of CASP8. Interacts (via CARD domain) with BAD(via BH3 domain); preventing the association of BAD with BCL2. Interacts directly (via CARD domain) with TNFRSF1A; inhibits TNF-signaling pathway (By similarity).By similarity1 Publication4 Publications

GO - Molecular functioni

  • caspase binding Source: UniProtKB
  • death effector domain binding Source: UniProtKB
  • kinase binding Source: UniProtKB
  • phosphatase binding Source: UniProtKB

Protein-protein interaction databases

IntActiQ62881, 1 interactor

Structurei

3D structure databases

ProteinModelPortaliQ62881
SMRiQ62881
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini4 – 95CARDPROSITE-ProRule annotationAdd BLAST92

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni20 – 70Essential for interaction with BAX1 PublicationAdd BLAST51

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi107 – 219Glu/Pro-richAdd BLAST113

Domaini

CARD is critical for both extrinsic and intrinsic apoptotic pathways (PubMed:15383280). CARD domain mediates a protective effect against myocardial ischemia/reperfusion, oxidative stress and TNF-induced necrosis (By similarity). The calcium binding domain plays a protective role in calcium-mediated cell death (By similarity).By similarity1 Publication

Phylogenomic databases

eggNOGiENOG410J0R1 Eukaryota
ENOG4111BHK LUCA
HOGENOMiHOG000113820
HOVERGENiHBG029007
InParanoidiQ62881
PhylomeDBiQ62881

Family and domain databases

InterProiView protein in InterPro
IPR001315 CARD
IPR011029 DEATH-like_dom_sf
PfamiView protein in Pfam
PF00619 CARD, 1 hit
SMARTiView protein in SMART
SM00114 CARD, 1 hit
SUPFAMiSSF47986 SSF47986, 1 hit
PROSITEiView protein in PROSITE
PS50209 CARD, 1 hit

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q62881-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MGNMQERPSE TIDRERKRLV ETLQADSGLL LDALVARGVL TGPEYEALDA
60 70 80 90 100
LPDAERRVRR LLLLVQSKGE AACQELLRCA QQTVSMPDPA WDWQHVGPGY
110 120 130 140 150
RDRSYDPPCP GHWTPEAPSS GTTCPGLPRA SEEEEIGGPE DSEAVQPRTP
160 170 180 190 200
EEPELEAEAT KGDEPDLEQE MEPEPEPEVE PEPEPEPEPE PEPEPEPEPE
210 220
PEPEREPDFQ EGDESEGCEN T
Length:221
Mass (Da):24,577
Last modified:November 1, 1996 - v1
Checksum:iA7661C9040B2CD4D
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U40627 mRNA Translation: AAB05667.1
PIRiS70009
RefSeqiNP_445968.2, NM_053516.2
UniGeneiRn.86956

Genome annotation databases

GeneIDi85383
KEGGirno:85383
UCSCiRGD:708558 rat

Similar proteinsi

Entry informationi

Entry nameiNOL3_RAT
AccessioniPrimary (citable) accession number: Q62881
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 2, 2002
Last sequence update: November 1, 1996
Last modified: May 23, 2018
This is version 102 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

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