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Protein

Angiopoietin-related protein 3

Gene

ANGPTL3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Acts in part as a hepatokine that is involved in regulation of lipid and glucose metabolism (PubMed:11788823, PubMed:12909640, PubMed:23661675, PubMed:25495645). Proposed to play a role in the trafficking of energy substrates to either storage or oxidative tissues in response to food intake (By similarity). Has a stimulatory effect on plasma triglycerides (TG), which is achieved by suppressing plasma TG clearance via inhibition of LPL activity. The inhibition of LPL activity appears to be an indirect mechanism involving recruitment of proprotein convertases PCSK6 and FURIN to LPL leading to cleavage and dissociation of LPL from the cell surface; the function does not require ANGPTL3 proteolytic cleavage but seems to be mediated by the N-terminal domain, and is not inhibited by GPIHBP1 (PubMed:12097324, PubMed:19318355, PubMed:20581395). Can inhibit endothelial lipase, causing increased plasma levels of high density lipoprotein (HDL) cholesterol and phospholipids (PubMed:17110602, PubMed:19028676). Can bind to adipocytes to activate lipolysis, releasing free fatty acids and glycerol (PubMed:12565906). Suppresses LPL specifically in oxidative tissues which is required to route very low density lipoprotein (VLDL)-TG to white adipose tissue (WAT) for storage in response to food; the function may involve cooperation with circulating, liver-derived ANGPTL8 and ANGPTL4 expression in WAT (By similarity). Contributes to lower plasma levels of low density lipoprotein (LDL)-cholesterol by a mechanism that is independent of the canonical pathway implicating APOE and LDLR. May stimulate hypothalamic LPL activity (By similarity).By similarity1 Publication10 Publications
ANGPTL3(17-221): In vitro inhibits LPL activity; not effective on GPIHBP1-stabilized LPL.1 Publication
Involved in angiogenesis. Binds to endothelial cells via integrin alpha-V/beta-3 (ITGAV:ITGB3), activates FAK, MAPK and Akt signaling pathways and induces cell adhesion and cell migration (PubMed:11877390). Secreted from podocytes, may modulate properties of glomerular endothelial cells involving integrin alpha-V/beta-3 and Akt signaling (PubMed:18535744). May increase the motility of podocytes. May induce actin filament rearrangements in podocytes implicating integrin alpha-V/beta-3 and Rac1 activation. Binds to hematopoietic stem cells (HSC) and is involved in the regulation of HSC activity probably implicating down-regulation of IKZF1/IKAROS (By similarity).By similarity2 Publications

GO - Molecular functioni

  • enzyme inhibitor activity Source: UniProtKB
  • growth factor activity Source: BHF-UCL
  • heparin binding Source: UniProtKB-KW
  • integrin binding Source: UniProtKB
  • phospholipase inhibitor activity Source: BHF-UCL

GO - Biological processi

  • acylglycerol homeostasis Source: BHF-UCL
  • angiogenesis Source: UniProtKB-KW
  • artery morphogenesis Source: BHF-UCL
  • cell-matrix adhesion Source: UniProtKB
  • cholesterol homeostasis Source: BHF-UCL
  • cholesterol metabolic process Source: BHF-UCL
  • fatty acid metabolic process Source: BHF-UCL
  • glycerol metabolic process Source: BHF-UCL
  • integrin-mediated signaling pathway Source: UniProtKB
  • lipid homeostasis Source: BHF-UCL
  • lipid storage Source: BHF-UCL
  • negative regulation of lipoprotein lipase activity Source: BHF-UCL
  • negative regulation of phospholipase activity Source: BHF-UCL
  • phospholipid catabolic process Source: BHF-UCL
  • phospholipid homeostasis Source: BHF-UCL
  • phospholipid metabolic process Source: BHF-UCL
  • positive regulation of angiogenesis Source: UniProtKB
  • positive regulation of cell migration Source: UniProtKB
  • positive regulation of lipid catabolic process Source: BHF-UCL
  • response to hormone Source: Ensembl
  • signal transduction Source: BHF-UCL
  • triglyceride homeostasis Source: BHF-UCL
Complete GO annotation...

Keywords - Biological processi

Angiogenesis, Cell adhesion, Lipid metabolism

Keywords - Ligandi

Heparin-binding

Enzyme and pathway databases

BioCyciZFISH:ENSG00000132855-MONOMER.
ReactomeiR-HSA-174800. Chylomicron-mediated lipid transport.

Names & Taxonomyi

Protein namesi
Recommended name:
Angiopoietin-related protein 3
Alternative name(s):
Angiopoietin-5
Short name:
ANG-5
Angiopoietin-like protein 3
Cleaved into the following 2 chains:
Gene namesi
Name:ANGPTL3
Synonyms:ANGPT5
ORF Names:UNQ153/PRO179
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

HGNCiHGNC:491. ANGPTL3.

Subcellular locationi

GO - Cellular componenti

  • cell surface Source: BHF-UCL
  • early endosome Source: Ensembl
  • extracellular space Source: BHF-UCL
  • Golgi apparatus Source: Ensembl
  • lamellipodium Source: UniProtKB-SubCell
Complete GO annotation...

Keywords - Cellular componenti

Cell projection, Secreted

Pathology & Biotechi

Involvement in diseasei

Hypobetalipoproteinemia, familial, 2 (FHBL2)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA disorder of lipid metabolism characterized by less than 5th percentile age- and sex-specific levels of low density lipoproteins, and dietary fat malabsorption. Affected individuals present with combined hypolipidemia, consisting of extremely low plasma levels of LDL cholesterol, HDL cholesterol, and triglycerides.
See also OMIM:605019

May be involved in atherosclerosis. Plasma levels are closely associated with arterial wall thickness.

May be involved in nephrotic syndrome.

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi62 – 63HK → IN: Abolishes effect on plasma triglyceride level; when associated with N-65. 1 Publication2
Mutagenesisi63K → N: Abolishes inhibitory effect on LIPG/EL phospholipase activity; when associated with N-65. 1 Publication1
Mutagenesisi65K → N: Abolishes effect on plasma triglyceride level; when associated with 62-I-N-63. 1 Publication1
Mutagenesisi65K → N: Abolishes inhibitory effect on LIPG/EL phospholipase activity; when associated with N-63. 1 Publication1
Mutagenesisi204 – 205RR → TT: Abolishes proteolytical cleavage and effect on plasma triglyceride levels, keeps in vitro inactivation of LPL activity; when associated with S-221; S-224 and S-235. 1 Publication2
Mutagenesisi221R → ST: Abolishes proteolytical cleavage and effect on plasma triglyceride levels, keeps in vitro inactivation of LPL activity; when associated with 204-T-T-205; S-224 and S-235. 1 Publication1
Mutagenesisi224R → S: Abolishes proteolytical cleavage and effect on plasma triglyceride levels, keeps in vitro inactivation of LPL activity; when associated with 204-T-T-205; S-221 and S-235. 1 Publication1
Mutagenesisi235R → T: Abolishes proteolytical cleavage and effect on plasma triglyceride levels, keeps in vitro inactivation of LPL activity; when associated with 204-T-T-205; S-221 and S-224. 1 Publication1

Organism-specific databases

DisGeNETi27329.
MalaCardsiANGPTL3.
MIMi605019. phenotype.
OpenTargetsiENSG00000132855.
Orphaneti426. Familial hypobetalipoproteinemia.
PharmGKBiPA24796.

Polymorphism and mutation databases

DMDMi25008126.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 161 PublicationAdd BLAST16
ChainiPRO_000000912217 – 460Angiopoietin-related protein 3Add BLAST444
ChainiPRO_000043590317 – 224ANGPTL3(17-224)1 PublicationAdd BLAST208
ChainiPRO_000043590417 – 221ANGPTL3(17-221)1 PublicationAdd BLAST205

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi115N-linked (GlcNAc...)2 Publications1
Glycosylationi226O-linked (GalNAc)1 Publication1
Disulfide bondi246 ↔ 274PROSITE-ProRule annotation
Glycosylationi296N-linked (GlcNAc...)2 Publications1
Glycosylationi357N-linked (GlcNAc...)1 Publication1
Disulfide bondi394 ↔ 408PROSITE-ProRule annotation

Post-translational modificationi

O-glycosylated at Thr-226 by GALNT2; blocks processing and activation by proprotein convertases.2 Publications
In part proteolytically cleaved by proprotein convertases; proposed to be involved in activation.2 Publications

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

EPDiQ9Y5C1.
PaxDbiQ9Y5C1.
PeptideAtlasiQ9Y5C1.
PRIDEiQ9Y5C1.

PTM databases

iPTMnetiQ9Y5C1.
PhosphoSitePlusiQ9Y5C1.

Expressioni

Tissue specificityi

Expressed principally in liver. Weakly expressed in kidney. Binds to adipocytes. Increased expression and colocalization with activated ITGB3 in glomeruli of patients with nephrotic syndrome showing effaced podocyte foot processes (at protein level).3 Publications

Inductioni

Down-regulated by insulin.1 Publication

Gene expression databases

BgeeiENSG00000132855.
CleanExiHS_ANGPTL3.
GenevisibleiQ9Y5C1. HS.

Organism-specific databases

HPAiHPA038097.

Interactioni

Subunit structurei

Interacts with ANGPTL8. Interacts with ITGB3 (By similarity).By similarity1 Publication

GO - Molecular functioni

  • growth factor activity Source: BHF-UCL
  • integrin binding Source: UniProtKB

Protein-protein interaction databases

BioGridi118143. 5 interactors.
IntActiQ9Y5C1. 3 interactors.
STRINGi9606.ENSP00000360170.

Structurei

3D structure databases

ProteinModelPortaliQ9Y5C1.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini237 – 455Fibrinogen C-terminalPROSITE-ProRule annotationAdd BLAST219

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni17 – 207Sufficient to inhibit LIPG/EL phospholipase activity1 PublicationAdd BLAST191
Regioni17 – 165Sufficient to inhibit LPL lipase activity1 PublicationAdd BLAST149
Regioni32 – 56Required for inhibition of LPL lipase activity1 PublicationAdd BLAST25

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili85 – 210Sequence analysisAdd BLAST126

Domaini

The fibrinogen C-terminal domain is sufficient to mediate endothelial cell adhesion.1 Publication

Sequence similaritiesi

Contains 1 fibrinogen C-terminal domain.PROSITE-ProRule annotation

Keywords - Domaini

Coiled coil, Signal

Phylogenomic databases

eggNOGiKOG2579. Eukaryota.
ENOG410ZYS4. LUCA.
GeneTreeiENSGT00830000128240.
HOGENOMiHOG000015386.
HOVERGENiHBG001644.
InParanoidiQ9Y5C1.
OMAiFSTWDHK.
OrthoDBiEOG091G03M1.
PhylomeDBiQ9Y5C1.
TreeFamiTF336658.

Family and domain databases

CDDicd00087. FReD. 1 hit.
Gene3Di3.90.215.10. 1 hit.
4.10.530.10. 1 hit.
InterProiIPR014716. Fibrinogen_a/b/g_C_1.
IPR014715. Fibrinogen_a/b/g_C_2.
IPR002181. Fibrinogen_a/b/g_C_dom.
[Graphical view]
PfamiPF00147. Fibrinogen_C. 1 hit.
[Graphical view]
SMARTiSM00186. FBG. 1 hit.
[Graphical view]
SUPFAMiSSF56496. SSF56496. 1 hit.
PROSITEiPS51406. FIBRINOGEN_C_2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

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

Q9Y5C1-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MFTIKLLLFI VPLVISSRID QDNSSFDSLS PEPKSRFAML DDVKILANGL
60 70 80 90 100
LQLGHGLKDF VHKTKGQIND IFQKLNIFDQ SFYDLSLQTS EIKEEEKELR
110 120 130 140 150
RTTYKLQVKN EEVKNMSLEL NSKLESLLEE KILLQQKVKY LEEQLTNLIQ
160 170 180 190 200
NQPETPEHPE VTSLKTFVEK QDNSIKDLLQ TVEDQYKQLN QQHSQIKEIE
210 220 230 240 250
NQLRRTSIQE PTEISLSSKP RAPRTTPFLQ LNEIRNVKHD GIPAECTTIY
260 270 280 290 300
NRGEHTSGMY AIRPSNSQVF HVYCDVISGS PWTLIQHRID GSQNFNETWE
310 320 330 340 350
NYKYGFGRLD GEFWLGLEKI YSIVKQSNYV LRIELEDWKD NKHYIEYSFY
360 370 380 390 400
LGNHETNYTL HLVAITGNVP NAIPENKDLV FSTWDHKAKG HFNCPEGYSG
410 420 430 440 450
GWWWHDECGE NNLNGKYNKP RAKSKPERRR GLSWKSQNGR LYSIKSTKML
460
IHPTDSESFE
Length:460
Mass (Da):53,637
Last modified:November 1, 1999 - v1
Checksum:i6279465FEEB91F56
GO

Sequence cautioni

The sequence AAH07059 differs from that shown. Contaminating sequence. Potential poly-A sequence.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti134L → P in BAG37708 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07567063K → T Associated with low plasma triglyceride level, fails to suppress LPL activity in vitro. 1 PublicationCorresponds to variant rs146749211dbSNPEnsembl.1
Natural variantiVAR_07567191E → G Associated with low plasma triglyceride level, fails to suppress LPL activity in vitro. 1 PublicationCorresponds to variant rs139334976dbSNPEnsembl.1
Natural variantiVAR_067283127L → F.1 PublicationCorresponds to variant rs72649573dbSNPEnsembl.1
Natural variantiVAR_075672164L → F Associated with low plasma triglyceride level, fails to suppress LPL activity in vitro. 1 PublicationCorresponds to variant rs775976787dbSNPEnsembl.1
Natural variantiVAR_075673173N → S Associated with low plasma triglyceride level, fails to suppress LPL activity in vitro, no effect on protein secretion. 2 PublicationsCorresponds to variant rs149624466dbSNPEnsembl.1
Natural variantiVAR_075674259M → T Common allele in African americans, associated with low plasma triglyceride level, fails to suppress LPL activity in vitro. 1 PublicationCorresponds to variant rs77871363dbSNPEnsembl.1
Natural variantiVAR_075675288R → Q Abolishes protein secretion, associated with low plasma triglyceride level. 1 PublicationCorresponds to variant rs763904695dbSNPEnsembl.1
Natural variantiVAR_075676288Missing Abolishes protein secretion, associated with low plasma triglyceride level. 1 Publication1
Natural variantiVAR_075677292S → P Abolishes protein secretion, associated with low plasma triglyceride level. 1 PublicationCorresponds to variant rs138899888dbSNPEnsembl.1
Natural variantiVAR_075678344Y → S Abolishes protein secretion, associated with low plasma triglyceride level. 1 Publication1
Natural variantiVAR_075679375E → K Abolishes protein secretion, associated with low plasma triglyceride level. 2 PublicationsCorresponds to variant rs768802285dbSNPEnsembl.1
Natural variantiVAR_075680417Y → C Abolishes protein secretion, associated with low plasma triglyceride level. 1 PublicationCorresponds to variant rs376210525dbSNPEnsembl.1
Natural variantiVAR_049071418N → Y.Corresponds to variant rs4145257dbSNPEnsembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF152562 mRNA. Translation: AAD34156.1.
AY358273 mRNA. Translation: AAQ88640.1.
AK315304 mRNA. Translation: BAG37708.1.
AY569015 Genomic DNA. Translation: AAS66984.1.
FJ515851 Genomic DNA. Translation: ACS13743.1.
CH471059 Genomic DNA. Translation: EAX06583.1.
BC007059 mRNA. Translation: AAH07059.1. Sequence problems.
BC058287 mRNA. Translation: AAH58287.1.
CCDSiCCDS622.1.
RefSeqiNP_055310.1. NM_014495.3.
UniGeneiHs.209153.

Genome annotation databases

EnsembliENST00000371129; ENSP00000360170; ENSG00000132855.
GeneIDi27329.
KEGGihsa:27329.
UCSCiuc001das.3. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF152562 mRNA. Translation: AAD34156.1.
AY358273 mRNA. Translation: AAQ88640.1.
AK315304 mRNA. Translation: BAG37708.1.
AY569015 Genomic DNA. Translation: AAS66984.1.
FJ515851 Genomic DNA. Translation: ACS13743.1.
CH471059 Genomic DNA. Translation: EAX06583.1.
BC007059 mRNA. Translation: AAH07059.1. Sequence problems.
BC058287 mRNA. Translation: AAH58287.1.
CCDSiCCDS622.1.
RefSeqiNP_055310.1. NM_014495.3.
UniGeneiHs.209153.

3D structure databases

ProteinModelPortaliQ9Y5C1.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi118143. 5 interactors.
IntActiQ9Y5C1. 3 interactors.
STRINGi9606.ENSP00000360170.

PTM databases

iPTMnetiQ9Y5C1.
PhosphoSitePlusiQ9Y5C1.

Polymorphism and mutation databases

DMDMi25008126.

Proteomic databases

EPDiQ9Y5C1.
PaxDbiQ9Y5C1.
PeptideAtlasiQ9Y5C1.
PRIDEiQ9Y5C1.

Protocols and materials databases

DNASUi27329.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000371129; ENSP00000360170; ENSG00000132855.
GeneIDi27329.
KEGGihsa:27329.
UCSCiuc001das.3. human.

Organism-specific databases

CTDi27329.
DisGeNETi27329.
GeneCardsiANGPTL3.
HGNCiHGNC:491. ANGPTL3.
HPAiHPA038097.
MalaCardsiANGPTL3.
MIMi604774. gene.
605019. phenotype.
neXtProtiNX_Q9Y5C1.
OpenTargetsiENSG00000132855.
Orphaneti426. Familial hypobetalipoproteinemia.
PharmGKBiPA24796.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG2579. Eukaryota.
ENOG410ZYS4. LUCA.
GeneTreeiENSGT00830000128240.
HOGENOMiHOG000015386.
HOVERGENiHBG001644.
InParanoidiQ9Y5C1.
OMAiFSTWDHK.
OrthoDBiEOG091G03M1.
PhylomeDBiQ9Y5C1.
TreeFamiTF336658.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000132855-MONOMER.
ReactomeiR-HSA-174800. Chylomicron-mediated lipid transport.

Miscellaneous databases

GeneWikiiANGPTL3.
GenomeRNAii27329.
PROiQ9Y5C1.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000132855.
CleanExiHS_ANGPTL3.
GenevisibleiQ9Y5C1. HS.

Family and domain databases

CDDicd00087. FReD. 1 hit.
Gene3Di3.90.215.10. 1 hit.
4.10.530.10. 1 hit.
InterProiIPR014716. Fibrinogen_a/b/g_C_1.
IPR014715. Fibrinogen_a/b/g_C_2.
IPR002181. Fibrinogen_a/b/g_C_dom.
[Graphical view]
PfamiPF00147. Fibrinogen_C. 1 hit.
[Graphical view]
SMARTiSM00186. FBG. 1 hit.
[Graphical view]
SUPFAMiSSF56496. SSF56496. 1 hit.
PROSITEiPS51406. FIBRINOGEN_C_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiANGL3_HUMAN
AccessioniPrimary (citable) accession number: Q9Y5C1
Secondary accession number(s): A0JLS0, B1ALJ0, B2RCW1
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 8, 2002
Last sequence update: November 1, 1999
Last modified: November 30, 2016
This is version 148 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Miscellaneous

Was suggested to inhibit LPL through a direct mechanism; however, the necessary concentration to achieve in vitro inhibition is at least 30-fold higher than ANGPTL3 plasma concentration.2 Publications

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. 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.