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Q96AD5 (PLPL2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 97. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Patatin-like phospholipase domain-containing protein 2

EC=3.1.1.3
Alternative name(s):
Adipose triglyceride lipase
Calcium-independent phospholipase A2
Desnutrin
IPLA2-zeta
Pigment epithelium-derived factor
TTS2.2
Transport-secretion protein 2
Short name=TTS2
Gene names
Name:PNPLA2
Synonyms:ATGL
ORF Names:FP17548
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length504 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Catalyzes the initial step in triglyceride hydrolysis in adipocyte and non-adipocyte lipid droplets. Also has acylglycerol transacylase activity. May act coordinately with LIPE/HLS within the lipolytic cascade. Regulates adiposome size and may be involved in the degradation of adiposomes. May play an important role in energy homeostasis. May play a role in the response of the organism to starvation, enhancing hydrolysis of triglycerides and providing free fatty acids to other tissues to be oxidized in situations of energy depletion. Ref.1 Ref.6 Ref.10

Catalytic activity

Triacylglycerol + H2O = diacylglycerol + a carboxylate.

Enzyme regulation

Inhibited by BEL ((E)-6-(bromomethylene)-3-(1-naphthalenyl)-2H-tetrahydropyran-2-one), a suicide substrate inhibitor. No differences in enzymatic activity that uses (1,2-dilinoleoyl)-phosphatidylcholine as substrate was detected in the presence or absence of ATP. Activated by ABHD5 and SERPINF1. Ref.6 Ref.11

Pathway

Glycerolipid metabolism; triacylglycerol degradation.

Subunit structure

Interacts with ABHD5; this association stimulates PNPLA2 triglyceride hydrolase activity By similarity. Interacts with SERPINF1; interacts at one site of interaction. Despite a colocalization in lipid droplets, it probably does not interact with PLIN By similarity. Interacts with PLIN5; prevents interaction with ABHD5 By similarity. Ref.11

Subcellular location

Lipid droplet. Cell membrane; Single-pass type II membrane protein Ref.10 Ref.11.

Tissue specificity

Highest expression in adipose tissue. Also detected in heart, skeletal muscle, and portions of the gastrointestinal tract. Detected in normal retina and retinoblastoma cells. Detected in retinal pigment epithelium and, at lower intensity, in the inner segments of photoreceptors and in the ganglion cell layer of the neural retina (at protein level). Ref.1 Ref.7 Ref.8 Ref.11

Developmental stage

Induced during differentiation of primary preadipocytes to adipocytes. Expression increased from fetal to adult in retinal pigment epithelium. Ref.7 Ref.9 Ref.11

Post-translational modification

Phosphorylation at Ser-404 by PKA is increased during fasting and moderate intensity exercise, and moderately increases lipolytic activity By similarity. Phosphorylation at Ser-404 is increased upon beta-adrenergic stimulation.

Polymorphism

Genetic variations in PNPLA2 may be associated with plasma free fatty acids, triglycerides levels, and fasting glucose concentrations.

Involvement in disease

Genetic variations in PNPLA2 may be associated with risk of diabetes mellitus type 2.

Neutral lipid storage disease with myopathy (NLSDM) [MIM:610717]: Neutral lipid storage disorder (NLSD) with myopathy but without ichthyosis. NLSDs are characterized by the presence of triglyceride-containing cytoplasmic droplets in leukocytes and in other tissues, including bone marrow, skin, and muscle. Individuals with NLSDM did not show obesity, in spite of a defect in triglyceride degradation in fibroblasts and in marked triglyceride storage in liver, muscles, and other visceral cells.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.16

Sequence similarities

Contains 1 patatin domain.

Biophysicochemical properties

pH dependence:

Optimum pH is 7.5 with (1,2-dilinoleoyl)-phosphatidylcholine as substrate. Ref.11

Sequence caution

The sequence AAP34448.1 differs from that shown. Reason: Frameshift at position 501.

The sequence CAC01131.1 differs from that shown. Reason: Erroneous initiation.

The sequence CAC01132.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
   Biological processLipid degradation
Lipid metabolism
   Cellular componentCell membrane
Lipid droplet
Membrane
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDisease mutation
   DomainSignal-anchor
Transmembrane
Transmembrane helix
   Molecular functionHydrolase
   PTMGlycoprotein
Phosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processacylglycerol acyl-chain remodeling

Traceable author statement. Source: Reactome

glycerophospholipid biosynthetic process

Traceable author statement. Source: Reactome

negative regulation of sequestering of triglyceride

Inferred from direct assay PubMed 16679289. Source: UniProtKB

phospholipid metabolic process

Traceable author statement. Source: Reactome

positive regulation of triglyceride catabolic process

Inferred from direct assay PubMed 16679289. Source: UniProtKB

small molecule metabolic process

Traceable author statement. Source: Reactome

triglyceride catabolic process

Inferred from electronic annotation. Source: UniProtKB-UniPathway

   Cellular_componentcytosol

Inferred from electronic annotation. Source: Ensembl

endoplasmic reticulum membrane

Traceable author statement. Source: Reactome

integral component of membrane

Inferred from electronic annotation. Source: UniProtKB-KW

intracellular membrane-bounded organelle

Inferred from direct assay. Source: HPA

lipid particle

Inferred from direct assay PubMed 21498505. Source: UniProtKB

plasma membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functiontriglyceride lipase activity

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q96AD5-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: Q96AD5-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-324: Missing.
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 504504Patatin-like phospholipase domain-containing protein 2
PRO_0000292527

Regions

Topological domain1 – 88Cytoplasmic Potential
Transmembrane9 – 2921Helical; Signal-anchor for type II membrane protein; Potential
Topological domain30 – 504475Lumenal Potential
Domain10 – 179170Patatin
Motif45 – 495GXSXG

Sites

Active site471

Amino acid modifications

Modified residue3721Phosphoserine; in vitro By similarity
Modified residue4041Phosphoserine; by PKA Ref.14
Modified residue4281Phosphoserine Ref.13
Glycosylation391N-linked (GlcNAc...) Potential

Natural variations

Alternative sequence1 – 324324Missing in isoform 2.
VSP_026421
Natural variant1951P → L in NLSDM. Ref.16
VAR_032995
Natural variant2191L → F. Ref.15
VAR_032996
Natural variant2521N → K. Ref.15
Corresponds to variant rs140201358 [ dbSNP | Ensembl ].
VAR_032997
Natural variant4811L → P. Ref.2 Ref.4 Ref.15
Corresponds to variant rs1138693 [ dbSNP | Ensembl ].
VAR_032998

Experimental info

Mutagenesis471S → A: Reduces rate of lipid hydrolysis; does not affect the localization around the rim of the adiposomes. Ref.8 Ref.10
Sequence conflict1631R → G in AAC09354. Ref.5
Sequence conflict2961I → V in AAW81962. Ref.1
Sequence conflict3331A → G in AAP34448. Ref.3
Sequence conflict3511R → C in AAW81962. Ref.1
Sequence conflict4021V → L in CAC01131. Ref.2
Sequence conflict4021V → L in CAC01132. Ref.2
Sequence conflict4191L → P in AAW81962. Ref.1

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified December 1, 2001. Version 1.
Checksum: D9C16F942AB0B3C7

FASTA50455,316
        10         20         30         40         50         60 
MFPREKTWNI SFAGCGFLGV YYVGVASCLR EHAPFLVANA THIYGASAGA LTATALVTGV 

        70         80         90        100        110        120 
CLGEAGAKFI EVSKEARKRF LGPLHPSFNL VKIIRSFLLK VLPADSHEHA SGRLGISLTR 

       130        140        150        160        170        180 
VSDGENVIIS HFNSKDELIQ ANVCSGFIPV YCGLIPPSLQ GVRYVDGGIS DNLPLYELKN 

       190        200        210        220        230        240 
TITVSPFSGE SDICPQDSST NIHELRVTNT SIQFNLRNLY RLSKALFPPE PLVLREMCKQ 

       250        260        270        280        290        300 
GYRDGLRFLQ RNGLLNRPNP LLALPPARPH GPEDKDQAVE SAQAEDYSQL PGEDHILEHL 

       310        320        330        340        350        360 
PARLNEALLE ACVEPTDLLT TLSNMLPVRL ATAMMVPYTL PLESALSFTI RLLEWLPDVP 

       370        380        390        400        410        420 
EDIRWMKEQT GSICQYLVMR AKRKLGRHLP SRLPEQVELR RVQSLPSVPL SCAAYREALP 

       430        440        450        460        470        480 
GWMRNNLSLG DALAKWEECQ RQLLLGLFCT NVAFPPEALR MRAPADPAPA PADPASPQHQ 

       490        500 
LAGPAPLLST PAPEARPVIG ALGL 

« Hide

Isoform 2 [UniParc].

Checksum: 00655EB8A70EF89A
Show »

FASTA18019,875

References

« Hide 'large scale' references
[1]"Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase."
Zimmermann R., Strauss J.G., Haemmerle G., Schoiswohl G., Birner-Gruenberger R., Riederer M., Lass A., Neuberger G., Eisenhaber F., Hermetter A., Zechner R.
Science 306:1383-1386(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY.
[2]"TTS-2, a novel protein implicated in vesicular transport of the cell surface receptor ICAM-3."
Strahl T., Shingler W.H., Lammiman M., Gregory C.D., Leach L., Matthias P., Nielsen P.J., Shaw P.E.
Submitted (JUN-2000) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT PRO-481.
[3]"Large-scale cDNA transfection screening for genes related to cancer development and progression."
Wan D., Gong Y., Qin W., Zhang P., Li J., Wei L., Zhou X., Li H., Qiu X., Zhong F., He L., Yu J., Yao G., Jiang H., Qian L., Yu Y., Shu H., Chen X. expand/collapse author list , Xu H., Guo M., Pan Z., Chen Y., Ge C., Yang S., Gu J.
Proc. Natl. Acad. Sci. U.S.A. 101:15724-15729(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
[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] (ISOFORM 1), VARIANT PRO-481.
Tissue: Brain and Eye.
[5]Yu W., Gibbs R.A.
Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 94-504 (ISOFORM 1).
Tissue: Brain.
[6]"Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities."
Jenkins C.M., Mancuso D.J., Yan W., Sims H.F., Gibson B., Gross R.W.
J. Biol. Chem. 279:48968-48975(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, ENZYME REGULATION.
[7]"Adipocyte lipases and defect of lipolysis in human obesity."
Langin D., Dicker A., Tavernier G., Hoffstedt J., Mairal A., Ryden M., Arner E., Sicard A., Jenkins C.M., Viguerie N., van Harmelen V., Gross R.W., Holm C., Arner P.
Diabetes 54:3190-3197(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: DEVELOPMENTAL STAGE, TISSUE SPECIFICITY.
[8]"Expression, regulation, and triglyceride hydrolase activity of Adiponutrin family members."
Lake A.C., Sun Y., Li J.-L., Kim J.E., Johnson J.W., Li D., Revett T., Shih H.H., Liu W., Paulsen J.E., Gimeno R.E.
J. Lipid Res. 46:2477-2487(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY, MUTAGENESIS OF SER-47.
[9]"The adipose tissue triglyceride lipase ATGL/PNPLA2 is downregulated by insulin and TNF-alpha in 3T3-L1 adipocytes and is a target for transactivation by PPARgamma."
Kim J.Y., Tillison K., Lee J.-H., Rearick D.A., Smas C.M.
Am. J. Physiol. 291:E115-E127(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: DEVELOPMENTAL STAGE.
[10]"ATGL has a key role in lipid droplet/adiposome degradation in mammalian cells."
Smirnova E., Goldberg E.B., Makarova K.S., Lin L., Brown W.J., Jackson C.L.
EMBO Rep. 7:106-113(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF SER-47.
[11]"Identification of a lipase-linked cell membrane receptor for pigment epithelium-derived factor."
Notari L., Baladron V., Aroca-Aguilar J.D., Balko N., Heredia R., Meyer C., Notario P.M., Saravanamuthu S., Nueda M.-L., Sanchez-Sanchez F., Escribano J., Laborda J., Becerra S.P.
J. Biol. Chem. 281:38022-38037(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: ENZYME REGULATION, BIOPHYSICOCHEMICAL PROPERTIES, INTERACTION WITH SERPINF1, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE.
[12]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[13]"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation."
Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.
Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-428, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[14]"Identification and functional characterization of protein kinase A phosphorylation sites in the major lipolytic protein, adipose triglyceride lipase."
Pagnon J., Matzaris M., Stark R., Meex R.C., Macaulay S.L., Brown W., O'Brien P.E., Tiganis T., Watt M.J.
Endocrinology 153:4278-4289(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-404.
[15]"The ATGL gene is associated with free fatty acids, triglycerides, and type 2 diabetes."
Schoenborn V., Heid I.M., Vollmert C., Lingenhel A., Adams T.D., Hopkins P.N., Illig T., Zimmermann R., Zechner R., Hunt S.C., Kronenberg F.
Diabetes 55:1270-1275(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS PHE-219; LYS-252 AND PRO-481, POLYMORPHISM, ASSOCIATION WITH DIABETES MELLITUS TYPE 2.
[16]"The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy."
Fischer J., Lefevre C., Morava E., Mussini J.-M., Laforet P., Negre-Salvayre A., Lathrop M., Salvayre R.
Nat. Genet. 39:28-30(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT NLSDM LEU-195.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AY894804 mRNA. Translation: AAW81962.1.
AJ278475 mRNA. Translation: CAC01131.1. Different initiation.
AJ278476 mRNA. Translation: CAC01132.1. Different initiation.
AY203925 mRNA. Translation: AAP34448.1. Frameshift.
BC011958 mRNA. Translation: AAH11958.1.
BC017280 mRNA. Translation: AAH17280.1.
AF055000 mRNA. Translation: AAC09354.1.
CCDSCCDS7718.1. [Q96AD5-1]
RefSeqNP_065109.1. NM_020376.3. [Q96AD5-1]
UniGeneHs.654697.

3D structure databases

ProteinModelPortalQ96AD5.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid121370. 12 interactions.
IntActQ96AD5. 6 interactions.
MINTMINT-1184430.
STRING9606.ENSP00000337701.

PTM databases

PhosphoSiteQ96AD5.

Polymorphism databases

DMDM74731110.

Proteomic databases

MaxQBQ96AD5.
PaxDbQ96AD5.
PRIDEQ96AD5.

Protocols and materials databases

DNASU57104.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000336615; ENSP00000337701; ENSG00000177666. [Q96AD5-1]
GeneID57104.
KEGGhsa:57104.
UCSCuc001lrt.3. human. [Q96AD5-1]

Organism-specific databases

CTD57104.
GeneCardsGC11P000819.
HGNCHGNC:30802. PNPLA2.
HPAHPA055173.
MIM609059. gene.
610717. phenotype.
neXtProtNX_Q96AD5.
Orphanet98908. Neutral lipid storage myopathy.
PharmGKBPA134903083.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG261571.
HOVERGENHBG007046.
InParanoidQ96AD5.
KOK16816.
OMALVLREMC.
OrthoDBEOG7J9VQR.
PhylomeDBQ96AD5.
TreeFamTF314272.

Enzyme and pathway databases

ReactomeREACT_111217. Metabolism.
UniPathwayUPA00256.

Gene expression databases

BgeeQ96AD5.
CleanExHS_PNPLA2.
GenevestigatorQ96AD5.

Family and domain databases

InterProIPR016035. Acyl_Trfase/lysoPLipase.
IPR002641. Patatin/PLipase_A2-rel.
[Graphical view]
PfamPF01734. Patatin. 1 hit.
[Graphical view]
SUPFAMSSF52151. SSF52151. 1 hit.
ProtoNetSearch...

Other

ChiTaRSPNPLA2. human.
GeneWikiPNPLA2.
GenomeRNAi57104.
NextBio62941.
PROQ96AD5.
SOURCESearch...

Entry information

Entry namePLPL2_HUMAN
AccessionPrimary (citable) accession number: Q96AD5
Secondary accession number(s): O60643 expand/collapse secondary AC list , Q5EFF5, Q6XYE5, Q96ET6, Q9NQ61, Q9NQ62
Entry history
Integrated into UniProtKB/Swiss-Prot: June 26, 2007
Last sequence update: December 1, 2001
Last modified: July 9, 2014
This is version 97 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PATHWAY comments

Index of metabolic and biosynthesis pathways

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 11

Human chromosome 11: entries, gene names and cross-references to MIM