Q96AD5 (PLPL2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	504 AA.
Sequence status	Complete.
Protein existence	Evidence 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. 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 process	Lipid degradation Lipid metabolism
Cellular component	Cell membrane Lipid droplet Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Signal-anchor Transmembrane Transmembrane helix
Molecular function	Hydrolase
PTM	Glycoprotein Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	acylglycerol 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 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_component	cytosol Inferred from electronic annotation. Source: Compara endoplasmic reticulum membrane Traceable author statement. Source: Reactome integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW lipid particle Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	retinyl-palmitate esterase activity Inferred from electronic annotation. Source: EC triglyceride 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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 504	504	Patatin-like phospholipase domain-containing protein 2		PRO_0000292527
Regions
	Topological domain	1 – 8	8	Cytoplasmic Potential
	Transmembrane	9 – 29	21	Helical; Signal-anchor for type II membrane protein; Potential
	Topological domain	30 – 504	475	Lumenal Potential
	Domain	10 – 179	170	Patatin
	Motif	45 – 49	5	GXSXG
Sites
	Active site	47	1
Amino acid modifications
	Modified residue	372	1	Phosphoserine; in vitro By similarity
	Modified residue	404	1	Phosphoserine; by PKA Ref.14
	Modified residue	428	1	Phosphoserine Ref.13
	Glycosylation	39	1	N-linked (GlcNAc...) Potential
Natural variations
	Alternative sequence	1 – 324	324	Missing in isoform 2.		VSP_026421
	Natural variant	195	1	P → L in NLSDM. Ref.16		VAR_032995
	Natural variant	219	1	L → F. Ref.15		VAR_032996
	Natural variant	252	1	N → K. Ref.15		VAR_032997
	Natural variant	481	1	L → P. Ref.2 Ref.4 Ref.15 Corresponds to variant rs1138693 [ dbSNP | Ensembl ].		VAR_032998
Experimental info
	Mutagenesis	47	1	S → A: Reduces rate of lipid hydrolysis; does not affect the localization around the rim of the adiposomes. Ref.8 Ref.10
	Sequence conflict	163	1	R → G in AAC09354. Ref.5
	Sequence conflict	296	1	I → V in AAW81962. Ref.1
	Sequence conflict	333	1	A → G in AAP34448. Ref.3
	Sequence conflict	351	1	R → C in AAW81962. Ref.1
	Sequence conflict	402	1	V → L in CAC01131. Ref.2
	Sequence conflict	402	1	V → L in CAC01132. Ref.2
	Sequence conflict	419	1	L → P in AAW81962. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified December 1, 2001. Version 1. Checksum: D9C16F942AB0B3C7	FASTA	504	55,316
	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
	Isoform 2 [UniParc]. Checksum: 00655EB8A70EF89A	FASTA	180	19,875
	10 20 30 40 50 60 MLPVRLATAM MVPYTLPLES ALSFTIRLLE WLPDVPEDIR WMKEQTGSIC QYLVMRAKRK 70 80 90 100 110 120 LGRHLPSRLP EQVELRRVQS LPSVPLSCAA YREALPGWMR NNLSLGDALA KWEECQRQLL 130 140 150 160 170 180 LGLFCTNVAF PPEALRMRAP ADPAPAPADP ASPQHQLAGP APLLSTPAPE ARPVIGALGL

References

	« Hide 'large scale' referencesShow '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. , 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, MASS SPECTROMETRY.
[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.
IPI	IPI00550361. IPI00847143.
RefSeq	NP_065109.1. NM_020376.3.
UniGene	Hs.654697.
3D structure databases
ProteinModelPortal	Q96AD5.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q96AD5. 4 interactions.
MINT	MINT-1184430.
STRING	9606.ENSP00000337701.
PTM databases
PhosphoSite	Q96AD5.
Polymorphism databases
DMDM	74731110.
Proteomic databases
PaxDb	Q96AD5.
PRIDE	Q96AD5.
Protocols and materials databases
DNASU	57104.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000336615; ENSP00000337701; ENSG00000177666.
GeneID	57104.
KEGG	hsa:57104.
UCSC	uc001lrt.3. human.
Organism-specific databases
CTD	57104.
GeneCards	GC11P000808.
HGNC	HGNC:30802. PNPLA2.
MIM	609059. gene. 610717. phenotype.
neXtProt	NX_Q96AD5.
Orphanet	98908. Neutral lipid storage myopathy.
PharmGKB	PA134903083.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG261571.
HOVERGEN	HBG007046.
InParanoid	Q96AD5.
KO	K16816.
OMA	LVLREMC.
OrthoDB	EOG498V0W.
PhylomeDB	Q96AD5.
Enzyme and pathway databases
Reactome	REACT_111217. Metabolism.
UniPathway	UPA00256.
Gene expression databases
Bgee	Q96AD5.
CleanEx	HS_PNPLA2.
Genevestigator	Q96AD5.
Family and domain databases
InterPro	IPR016035. Acyl_Trfase/lysoPLipase. IPR002641. Patatin/PLipase_A2-rel. [Graphical view]
Pfam	PF01734. Patatin. 1 hit. [Graphical view]
SUPFAM	SSF52151. Acyl_Trfase/lysoPlipase. 1 hit.
ProtoNet	Search...
Other
ChiTaRS	PNPLA2. human.
GenomeRNAi	57104.
NextBio	62941.
SOURCE	Search...

Entry information

Entry name

PLPL2_HUMAN

Accession

Primary (citable) accession number: Q96AD5
Secondary accession number(s): O60643 , Q5EFF5, Q6XYE5, Q96ET6, Q9NQ61, Q9NQ62

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 26, 2007
Last sequence update:	December 1, 2001
Last modified:	May 1, 2013
This is version 86 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.