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Protein

Nucleolar protein 3

Gene

Nol3

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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 functionning 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 processing Source: UniProtKB-KW
  • 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
  • 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
Complete GO annotation...

Keywords - Biological processi

mRNA processing

Keywords - Ligandi

Calcium, 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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi708558. Nol3.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • membrane Source: UniProtKB-SubCell
  • mitochondrion Source: UniProtKB
  • sarcoplasmic reticulum Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Membrane, Mitochondrion, Sarcoplasmic reticulum

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi31 – 311L → 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 Publication
Mutagenesisi69 – 691G → 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 Publication
Mutagenesisi149 – 1491T → 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 Publications
Mutagenesisi149 – 1491T → D: Significantly enhances resistance against hydrogen peroxide- and induced by isoproterenol or aldosterone-induced cell death. 2 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methionineiRemovedBy similarity
Chaini2 – 221220Nucleolar protein 3PRO_0000144101Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Lipidationi2 – 21N-myristoyl glycineBy similarity
Modified residuei149 – 1491Phosphothreonine; by CK2Combined sources1 Publication

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 mithochondria 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.
PhosphoSiteiQ62881.

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 interaction.
STRINGi10116.ENSRNOP00000020908.

Structurei

3D structure databases

ProteinModelPortaliQ62881.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini4 – 9592CARDPROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni20 – 7051Essential for interaction with BAX1 PublicationAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi107 – 219113Glu/Pro-richAdd
BLAST

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

Sequence similaritiesi

Contains 1 CARD domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiENOG410J0R1. Eukaryota.
ENOG4111BHK. LUCA.
HOGENOMiHOG000113820.
HOVERGENiHBG029007.
InParanoidiQ62881.
PhylomeDBiQ62881.

Family and domain databases

Gene3Di1.10.533.10. 1 hit.
InterProiIPR001315. CARD.
IPR011029. DEATH-like_dom.
[Graphical view]
PfamiPF00619. CARD. 1 hit.
[Graphical view]
SMARTiSM00114. CARD. 1 hit.
[Graphical view]
SUPFAMiSSF47986. SSF47986. 1 hit.
PROSITEiPS50209. CARD. 1 hit.
[Graphical view]

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.

Cross-referencesi

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.

3D structure databases

ProteinModelPortaliQ62881.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiQ62881. 1 interaction.
STRINGi10116.ENSRNOP00000020908.

PTM databases

iPTMnetiQ62881.
PhosphoSiteiQ62881.

Proteomic databases

PaxDbiQ62881.
PRIDEiQ62881.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi85383.
KEGGirno:85383.
UCSCiRGD:708558. rat.

Organism-specific databases

CTDi8996.
RGDi708558. Nol3.

Phylogenomic databases

eggNOGiENOG410J0R1. Eukaryota.
ENOG4111BHK. LUCA.
HOGENOMiHOG000113820.
HOVERGENiHBG029007.
InParanoidiQ62881.
PhylomeDBiQ62881.

Miscellaneous databases

PROiQ62881.

Family and domain databases

Gene3Di1.10.533.10. 1 hit.
InterProiIPR001315. CARD.
IPR011029. DEATH-like_dom.
[Graphical view]
PfamiPF00619. CARD. 1 hit.
[Graphical view]
SMARTiSM00114. CARD. 1 hit.
[Graphical view]
SUPFAMiSSF47986. SSF47986. 1 hit.
PROSITEiPS50209. CARD. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiNOL3_RAT
AccessioniPrimary (citable) accession number: Q62881
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 2, 2002
Last sequence update: November 1, 1996
Last modified: June 8, 2016
This is version 94 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.