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Protein

Nucleolar protein 3

Gene

Nol3

Organism
Mus musculus (Mouse)
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 (By similarity). Secondly by interacting with CASP8 in a mitochondria localization- and phosphorylation-dependent manner, limiting the amount of soluble CASP8 available for DISC-mediated activation (By similarity). 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:16505176) (PubMed:24312627). Inhibits calcium-mediated cell death by functionning as a cytosolic calcium buffer, dissociating its interaction with CASP8 and maintaining calcium homeostasis (By similarity). Negatively regulates oxidative stress-induced apoptosis by phosphorylation-dependent suppression of the mitochondria-mediated intrinsic pathway, by blocking CASP2 activation and BAX translocation (By similarity). Negatively regulates hypoxia-induced apoptosis in part by inhibiting the release of cytochrome c from mitochondria in a caspase-independent manner (By similarity). Also inhibits TNF-induced necrosis by preventing TNF-signaling pathway through TNFRSF1A interaction abrogating the recruitment of RIPK1 to complex I (PubMed:24440909). Finally through its role as apoptosis repressor, promotes vascular remodeling through inhibition of apoptosis and stimulation of proliferation, in response to hypoxia (PubMed:22082675). Inhibits too myoblast differentiation through caspase inhibition (By similarity).By similarity4 Publications

GO - Molecular functioni

  • calcium ion binding Source: MGI
  • caspase binding Source: MGI
  • cysteine-type endopeptidase inhibitor activity involved in apoptotic process Source: MGI
  • death effector domain binding Source: UniProtKB
  • death receptor binding Source: UniProtKB
  • identical protein binding Source: MGI
  • receptor binding Source: UniProtKB

GO - Biological processi

  • blood vessel remodeling Source: UniProtKB
  • cardiac muscle cell apoptotic process Source: UniProtKB
  • inhibition of cysteine-type endopeptidase activity involved in apoptotic process Source: MGI
  • intrinsic apoptotic signaling pathway Source: UniProtKB
  • mRNA splice site selection Source: MGI
  • negative regulation of apoptotic process Source: UniProtKB
  • negative regulation of cardiac muscle cell apoptotic process Source: UniProtKB
  • negative regulation of extrinsic apoptotic signaling pathway Source: MGI
  • negative regulation of mitochondrial membrane permeability involved in apoptotic process Source: UniProtKB
  • negative regulation of muscle atrophy Source: UniProtKB
  • negative regulation of necrotic cell death Source: UniProtKB
  • negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway Source: MGI
  • negative regulation of release of cytochrome c from mitochondria Source: MGI
  • negative regulation of striated muscle cell apoptotic process Source: UniProtKB
  • negative regulation of tumor necrosis factor-mediated signaling pathway Source: UniProtKB
  • protein oligomerization Source: MGI
  • regulation of gene expression Source: MGI
  • regulation of NF-kappaB import into nucleus Source: UniProtKB
  • release of sequestered calcium ion into cytosol by sarcoplasmic reticulum Source: MGI
  • response to hypoxia Source: MGI
  • response to injury involved in regulation of muscle adaptation Source: MGI
  • response to ischemia Source: UniProtKB
Complete GO annotation...

Keywords - Biological processi

mRNA processing

Keywords - Ligandi

Calcium, Metal-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Nucleolar protein 3Imported
Alternative name(s):
Apoptosis repressor with CARD1 Publication
Gene namesi
Name:Nol3
Synonyms:Arc
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 8

Organism-specific databases

MGIiMGI:1925938. Nol3.

Subcellular locationi

  • Cytoplasm By similarity
  • Mitochondrion By similarity
  • Sarcoplasmic reticulum By similarity
  • Membrane By similarity; Lipid-anchor By similarity

  • Note: Phosphorylation at Thr-149 results in translocation to mithochondria. Colocalized with mitochondria in response to oxidative stress.By similarity

GO - Cellular componenti

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

Keywords - Cellular componenti

Cytoplasm, Membrane, Mitochondrion, Sarcoplasmic reticulum

Pathology & Biotechi

Disruption phenotypei

Mice homozygous for the NOL3-null allele are born normally and externally indistinguishable from littermates of other genotypes. NOL3-null mice grew to adulthood without any abnormalities in their general health and appearance under resting conditions. Under biomechanical stress, NOL3-deficient mice develop accelerated cardiomyopathy which is characterized by reduced contractile function, cardiac enlargement, and myocardial fibrosis. Likewise, under ischemia/reperfusion injury of NOL3-deficient mice have a markedly increased myocardial infarct sizes (PubMed:16505176). Double homozygous knockout mice for NOL3 and SGCD have an enhanced myofiber death and subsequent dystrophic disease (PubMed:24312627).2 Publications

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi31 – 311L → F: Unable to inhibit TNF-induced necrosis; when associated with R-69. Unable to induce TNF nuclear translocation; when associated with R-69. 1 Publication
Mutagenesisi69 – 691G → R: Unable to inhibit TNF-induced necrosis; when associated with F-31. Unable to induce TNF nuclear translocation; when associated with F-31. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methionineiRemovedBy similarity
Chaini2 – 220219Nucleolar protein 3PRO_0000144100Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Lipidationi2 – 21N-myristoyl glycineBy similarity
Modified residuei149 – 1491Phosphothreonine; by CK2By similarity

Post-translational modificationi

Phosphorylation at Thr-149 is required for its antiapoptotic effect by blocking death-inducing signaling complex 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. Dephosphorylated at Thr-149 by calcineurin; doesn't inhibit the association between FADD and CASP8 and the consequent apoptosis.By similarity
Polyubiquitinated by MDM2; promoting proteasomal-dependent degradation in response to apoptotic stimuli.By similarity

Keywords - PTMi

Lipoprotein, Myristate, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiQ9D1X0.
PaxDbiQ9D1X0.
PRIDEiQ9D1X0.

PTM databases

iPTMnetiQ9D1X0.
PhosphoSiteiQ9D1X0.

Expressioni

Gene expression databases

BgeeiQ9D1X0.
ExpressionAtlasiQ9D1X0. baseline and differential.
GenevisibleiQ9D1X0. MM.

Interactioni

Subunit structurei

Oligomerizes (via CARD doamin) (By similarity). Interacts (via CARD domain) with CASP2; inhibits CASP2 activity in a phosphorylation-dependent manner (By similarity). 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 (By similarity). 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 (By similarity). Interacts (via CARD domain) with BBC3 (via BH3 domain); preventing the association of BBC3 with BCL2 and resulting in activation of CASP8 (By similarity). Interacts (via CARD domain) with BAD(via BH3 domain); preventing the association of BAD with BCL2 (By similarity). Interacts directly (via CARD domain) with TNFRSF1A; inhibits TNF-signaling pathway.By similarity2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Tra2aQ6PFR54EBI-913097,EBI-913075

GO - Molecular functioni

  • caspase binding Source: MGI
  • death effector domain binding Source: UniProtKB
  • death receptor binding Source: UniProtKB
  • identical protein binding Source: MGI
  • receptor binding Source: UniProtKB

Protein-protein interaction databases

IntActiQ9D1X0. 2 interactions.
STRINGi10090.ENSMUSP00000014920.

Structurei

3D structure databases

ProteinModelPortaliQ9D1X0.
SMRiQ9D1X0. Positions 5-83.
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 BAXBy similarityAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi132 – 21887Glu/Pro-richAdd
BLAST

Domaini

CARD is critical for both extrinsic and intrinsic apoptotic pathways (By similarity). CARD domain mediates a protective effect against myocardial ischemia/reperfusion, oxidative stress and TNF-induced necrosis (By similarity) (PubMed:24440909). 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.
GeneTreeiENSGT00510000049353.
HOGENOMiHOG000069910.
HOVERGENiHBG029007.
InParanoidiQ9D1X0.
OMAiWTPEAPS.
OrthoDBiEOG7Z69FW.
PhylomeDBiQ9D1X0.
TreeFamiTF336957.

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.

Q9D1X0-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MGNVQERPSE TIDRERKRLV ETLQADSGLL LDALVARGVL TGPEYEALDA
60 70 80 90 100
LPDAERRVRR LLLLVQSKGE AACQELLRCA QQTVRMPDPA WDWQHVGPGY
110 120 130 140 150
RNRSYDPSCP GHWTPEAPSS GTTCPELPRA SEQEEVGGPE GSEALQPRTP
160 170 180 190 200
EEPELEAEAT EGDEPDLEQE MNPEQEPEPE PEPEPEPEPE PEPEPEPEPE
210 220
PEPEPEPEPD FQEEDESEDS
Length:220
Mass (Da):24,568
Last modified:June 1, 2001 - v1
Checksum:iA4DCD57C1EB320A2
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK021023 mRNA. Translation: BAB32281.1.
CCDSiCCDS52657.1.
RefSeqiNP_084428.1. NM_030152.4.
XP_006531566.1. XM_006531503.1.
UniGeneiMm.475715.

Genome annotation databases

EnsembliENSMUST00000014920; ENSMUSP00000014920; ENSMUSG00000014776.
GeneIDi78688.
KEGGimmu:78688.
UCSCiuc009ncd.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK021023 mRNA. Translation: BAB32281.1.
CCDSiCCDS52657.1.
RefSeqiNP_084428.1. NM_030152.4.
XP_006531566.1. XM_006531503.1.
UniGeneiMm.475715.

3D structure databases

ProteinModelPortaliQ9D1X0.
SMRiQ9D1X0. Positions 5-83.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiQ9D1X0. 2 interactions.
STRINGi10090.ENSMUSP00000014920.

PTM databases

iPTMnetiQ9D1X0.
PhosphoSiteiQ9D1X0.

Proteomic databases

MaxQBiQ9D1X0.
PaxDbiQ9D1X0.
PRIDEiQ9D1X0.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000014920; ENSMUSP00000014920; ENSMUSG00000014776.
GeneIDi78688.
KEGGimmu:78688.
UCSCiuc009ncd.1. mouse.

Organism-specific databases

CTDi8996.
MGIiMGI:1925938. Nol3.

Phylogenomic databases

eggNOGiENOG410J0R1. Eukaryota.
ENOG4111BHK. LUCA.
GeneTreeiENSGT00510000049353.
HOGENOMiHOG000069910.
HOVERGENiHBG029007.
InParanoidiQ9D1X0.
OMAiWTPEAPS.
OrthoDBiEOG7Z69FW.
PhylomeDBiQ9D1X0.
TreeFamiTF336957.

Miscellaneous databases

ChiTaRSiNol3. mouse.
PROiQ9D1X0.
SOURCEiSearch...

Gene expression databases

BgeeiQ9D1X0.
ExpressionAtlasiQ9D1X0. baseline and differential.
GenevisibleiQ9D1X0. MM.

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...

Publicationsi

« Hide 'large scale' publications
  1. "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] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: C57BL/6J.
    Tissue: Adipose tissue.
  2. "Inhibition of both the extrinsic and intrinsic death pathways through nonhomotypic death-fold interactions."
    Nam Y.J., Mani K., Ashton A.W., Peng C.F., Krishnamurthy B., Hayakawa Y., Lee P., Korsmeyer S.J., Kitsis R.N.
    Mol. Cell 15:901-912(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH FADD; FAS; CASP8 AND BAX.
  3. "Apoptosis repressor with caspase recruitment domain is required for cardioprotection in response to biomechanical and ischemic stress."
    Donath S., Li P., Willenbockel C., Al-Saadi N., Gross V., Willnow T., Bader M., Martin U., Bauersachs J., Wollert K.C., Dietz R., von Harsdorf R.
    Circulation 113:1203-1212(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: DISRUPTION PHENOTYPE, FUNCTION.
  4. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Brain, Brown adipose tissue, Heart, Kidney, Lung, Pancreas and Spleen.
  5. "A critical role for the protein apoptosis repressor with caspase recruitment domain in hypoxia-induced pulmonary hypertension."
    Zaiman A.L., Damico R., Thoms-Chesley A., Files D.C., Kesari P., Johnston L., Swaim M., Mozammel S., Myers A.C., Halushka M., El-Haddad H., Shimoda L.A., Peng C.F., Hassoun P.M., Champion H.C., Kitsis R.N., Crow M.T.
    Circulation 124:2533-2542(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  6. "Apoptosis repressor with a CARD domain (ARC) restrains Bax-mediated pathogenesis in dystrophic skeletal muscle."
    Davis J., Kwong J.Q., Kitsis R.N., Molkentin J.D.
    PLoS ONE 8:E82053-E82053(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE.
  7. "A novel role for the apoptosis inhibitor ARC in suppressing TNFalpha-induced regulated necrosis."
    Kung G., Dai P., Deng L., Kitsis R.N.
    Cell Death Differ. 21:634-644(2014) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH TNFRSF1A, MUTAGENESIS OF LEU-31 AND GLY-69.

Entry informationi

Entry nameiNOL3_MOUSE
AccessioniPrimary (citable) accession number: Q9D1X0
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 2, 2002
Last sequence update: June 1, 2001
Last modified: June 8, 2016
This is version 105 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. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. 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.