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O43586 (PPIP1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 123. 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·Interactions·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Proline-serine-threonine phosphatase-interacting protein 1

Short name=PEST phosphatase-interacting protein 1
Alternative name(s):
CD2-binding protein 1
H-PIP
Gene names
Name:PSTPIP1
Synonyms:CD2BP1
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length416 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Involved in regulation of the actin cytoskeleton. May regulate WAS actin-bundling activity. Bridges the interaction between ABL1 and PTPN18 leading to ABL1 dephosphorylation. May play a role as a scaffold protein between PTPN12 and WAS and allow PTPN12 to dephosphorylate WAS. Has the potential to physically couple CD2 and CD2AP to WAS. Acts downstream of CD2 and CD2AP to recruit WAS to the T-cell:APC contact site so as to promote the actin polymerization required for synapse induction during T-cell activation By similarity. Down-regulates CD2-stimulated adhesion through the coupling of PTPN12 to CD2. Also has a role in innate immunity and the inflammatory response. Recruited to inflammasomes by MEFV. Induces formation of pyroptosomes, large supramolecular structures composed of oligomerized PYCARD dimers which form prior to inflammatory apoptosis. Binding to MEFV allows MEFV to bind to PYCARD and facilitates pyroptosome formation. Regulates endocytosis and cell migration in neutrophils. Ref.1 Ref.7 Ref.8 Ref.10 Ref.11

Subunit structure

Homodimer (Ref.11). Homotrimer (Ref.7). Interacts (via coiled-coil domain) with CD2AP, PTPN12 and PTPN18. Interacts (via SH3 domain) with ABL1 and WAS. Interacts (via SH3 and coiled-coil domains) with MEFV (via B-box zinc finger); the interaction allows binding of MEFV to PYCARD and facilitates formation of PYCARD pyroptosomes. Interacts with CD2, DNM2 and FASLG. Ref.1 Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11

Subcellular location

Cytoplasm. Cytoplasmcytoskeleton. Cell projectionlamellipodium By similarity. Cell projectionuropodium. Cytoplasmperinuclear region By similarity. Cleavage furrow By similarity. Note: During interphase, colocalizes with F-actin in the cortical cytoskeleton, lamellipodia, and stress fibers. In dividing cells, colocalizes with the F-actin rich cytokinetic cleavage furrow. Colocalized with WAS to filamentous structures within the cytoplasm. Colocalized with PTPN12 in the cytoplasm and the perinuclear region. Colocalized with CD2AP and WAS in the actin cytoskeleton. Colocalized with CD2, CD2AP and WAS at the site of T-cell:APC contact By similarity. In monocytes, forms a branched filamentous network in the cytoplasm. In migrating neutrophils, localizes most strongly to the trailing edge of the uropod where it colocalizes with PIP5K1C. In transfected cells, forms relatively straight filaments radiating out from the nucleus. Colocalizes with MEFV, particularly at the branch point of filaments. Filament formation requires an intact tubulin cytoskeleton. Ref.1 Ref.8 Ref.10 Ref.11

Tissue specificity

Highly expressed in the peripheral blood leukocytes, granulocytes and monocytes, namely in T-cells and natural killer cells, and in spleen. Weakly expressed in the thymus, small intestine, lung and placenta. Ref.1 Ref.6

Domain

The FCH domain is important for filament formation. The SH3 domain is not required for filament formation or localization to the uropod.

Post-translational modification

Dephosphorylated on Tyr-345 by PTPN18, this event negatively regulates the association of PSTPIP1 with SH2 domain-containing proteins as tyrosine kinase. Phosphorylation of Tyr-345 is probably required for subsequent phosphorylation at other tyrosine residues. Phosphorylation is induced by activation of the EGFR and PDGFR in a ABL1 dependent manner. The phosphorylation regulates the interaction with WAS and with MEFV By similarity.

Involvement in disease

PAPA syndrome (PAPAS) [MIM:604416]: Characterized by autosomal dominant inheritance of early-onset, primarily affecting skin and joint tissues. Recurring inflammatory episodes lead to accumulation of sterile, pyogenic, neutrophil-rich material within the affected joints, ultimately resulting in significant destruction.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.6 Ref.13 Ref.14

Sequence similarities

Contains 1 FCH domain.

Contains 1 SH3 domain.

Ontologies

Keywords
   Biological processCell adhesion
Endocytosis
Immunity
Inflammatory response
Innate immunity
   Cellular componentCell projection
Cytoplasm
Cytoskeleton
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDisease mutation
   DomainCoiled coil
SH3 domain
   PTMPhosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcell adhesion

Traceable author statement Ref.1. Source: ProtInc

endocytosis

Inferred from electronic annotation. Source: UniProtKB-KW

inflammatory response

Inferred from electronic annotation. Source: UniProtKB-KW

innate immune response

Traceable author statement. Source: Reactome

nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway

Traceable author statement. Source: Reactome

signal transduction

Traceable author statement Ref.1. Source: ProtInc

   Cellular_componentactomyosin contractile ring

Inferred from electronic annotation. Source: Ensembl

cleavage furrow

Inferred from electronic annotation. Source: UniProtKB-SubCell

cytosol

Traceable author statement. Source: Reactome

lamellipodium

Inferred from electronic annotation. Source: UniProtKB-SubCell

perinuclear region of cytoplasm

Inferred from electronic annotation. Source: UniProtKB-SubCell

stress fiber

Inferred from electronic annotation. Source: Ensembl

uropod

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionprotein binding

Inferred from physical interaction PubMed 16318909Ref.9PubMed 9422760. Source: IntAct

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

FASLGP480235EBI-1050964,EBI-495538
PTPN18Q999524EBI-1050964,EBI-1384210

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: O43586-1)

Also known as: CD2BP1L;

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: O43586-2)

Also known as: CD2BP1S;

The sequence of this isoform differs from the canonical sequence as follows:
     280-309: APVPYQNYYDREVTPLTSSPGIQPSCGMIK → GEVRLADSAAS

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 416416Proline-serine-threonine phosphatase-interacting protein 1
PRO_0000058539

Regions

Domain5 – 8278FCH
Domain359 – 41658SH3
Coiled coil166 – 21247 Potential

Amino acid modifications

Modified residue3451Phosphotyrosine By similarity

Natural variations

Alternative sequence280 – 30930APVPY…CGMIK → GEVRLADSAAS in isoform 2.
VSP_015627
Natural variant481Q → H. Ref.2
Corresponds to variant rs1141038 [ dbSNP | Ensembl ].
VAR_023515
Natural variant1061E → K. Ref.2
Corresponds to variant rs1141039 [ dbSNP | Ensembl ].
VAR_023516
Natural variant1461Q → H. Ref.2
Corresponds to variant rs1141041 [ dbSNP | Ensembl ].
VAR_023517
Natural variant1491R → L. Ref.2
Corresponds to variant rs1141042 [ dbSNP | Ensembl ].
VAR_023518
Natural variant1511A → S. Ref.2
Corresponds to variant rs1141043 [ dbSNP | Ensembl ].
VAR_023519
Natural variant1551E → D. Ref.2
Corresponds to variant rs1141044 [ dbSNP | Ensembl ].
VAR_023520
Natural variant1561Q → H. Ref.2
Corresponds to variant rs1141045 [ dbSNP | Ensembl ].
VAR_023521
Natural variant2301A → T in PAPAS; severely reduced binding with PTPN12; markedly increased binding to MEFV; accentuates IL1B secretion; no effect on filament formation; increased induction of MEFV in response to retroviral infection. Ref.6 Ref.7 Ref.11 Ref.13 Ref.14
Corresponds to variant rs28939381 [ dbSNP | Ensembl ].
VAR_023522
Natural variant2501E → K in PAPAS; no effect on filament formation. Ref.11 Ref.14
VAR_070635
Natural variant2501E → Q in PAPAS; severely reduced binding with PTPN12; markedly increased binding to MEFV; accentuates IL1B secretion; increased induction of MEFV in response to retroviral infection. Ref.6 Ref.7 Ref.13 Ref.14
Corresponds to variant rs28939089 [ dbSNP | Ensembl ].
VAR_023523

Experimental info

Mutagenesis2321W → A: Abolishes binding to MEFV. Cytoplasmic filaments are finer with fewer branches. Ref.6 Ref.11
Mutagenesis2661D → N: No effect on filament formation. Ref.11
Mutagenesis3451Y → F: Decreases binding to MEFV. Ref.6
Sequence conflict3671L → F in AAD00762. Ref.2

Secondary structure

............ 416
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (CD2BP1L) [UniParc].

Last modified June 1, 1998. Version 1.
Checksum: 97818150B3D5D600

FASTA41647,591
        10         20         30         40         50         60 
MMPQLQFKDA FWCRDFTAHT GYEVLLQRLL DGRKMCKDME ELLRQRAQAE ERYGKELVQI 

        70         80         90        100        110        120 
ARKAGGQTEI NSLRASFDSL KQQMENVGSS HIQLALTLRE ELRSLEEFRE RQKEQRKKYE 

       130        140        150        160        170        180 
AVMDRVQKSK LSLYKKAMES KKTYEQKCRD ADDAEQAFER ISANGHQKQV EKSQNKARQC 

       190        200        210        220        230        240 
KDSATEAERV YRQSIAQLEK VRAEWEQEHR TTCEAFQLQE FDRLTILRNA LWVHSNQLSM 

       250        260        270        280        290        300 
QCVKDDELYE EVRLTLEGCS IDADIDSFIQ AKSTGTEPPA PVPYQNYYDR EVTPLTSSPG 

       310        320        330        340        350        360 
IQPSCGMIKR FSGLLHGSPK TTSLAASAAS TETLTPTPER NEGVYTAIAV QEIQGNPASP 

       370        380        390        400        410 
AQEYRALYDY TAQNPDELDL SAGDILEVIL EGEDGWWTVE RNGQRGFVPG SYLEKL 

« Hide

Isoform 2 (CD2BP1S) [UniParc].

Checksum: 54D64A3AAE16A2FC
Show »

FASTA39745,354

References

« Hide 'large scale' references
[1]"A cdc15-like adaptor protein (CD2BP1) interacts with the CD2 cytoplasmic domain and regulates CD2-triggered adhesion."
Li J., Nishizawa K., An W., Hussey R.E., Lialios F.E., Salgia R., Sunder-Plassmann R., Reinherz E.L.
EMBO J. 17:7320-7336(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION, INTERACTION WITH CD2 AND PTPN12, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[2]"The human homologue of mouse PTP-PIP interactor protein."
Wilson L.A., Fields D., Cruz L., Lasky L., Friesen J., Siminovitch K.A.
Submitted (MAR-1997) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS HIS-48; LYS-106; HIS-146; LEU-149; SER-151; ASP-155 AND HIS-156.
[3]"Human protein factory for converting the transcriptome into an in vitro-expressed proteome."
Goshima N., Kawamura Y., Fukumoto A., Miura A., Honma R., Satoh R., Wakamatsu A., Yamamoto J., Kimura K., Nishikawa T., Andoh T., Iida Y., Ishikawa K., Ito E., Kagawa N., Kaminaga C., Kanehori K., Kawakami B. expand/collapse author list , Kenmochi K., Kimura R., Kobayashi M., Kuroita T., Kuwayama H., Maruyama Y., Matsuo K., Minami K., Mitsubori M., Mori M., Morishita R., Murase A., Nishikawa A., Nishikawa S., Okamoto T., Sakagami N., Sakamoto Y., Sasaki Y., Seki T., Sono S., Sugiyama A., Sumiya T., Takayama T., Takayama Y., Takeda H., Togashi T., Yahata K., Yamada H., Yanagisawa Y., Endo Y., Imamoto F., Kisu Y., Tanaka S., Isogai T., Imai J., Watanabe S., Nomura N.
Nat. Methods 5:1011-1017(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[4]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]"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).
Tissue: Brain.
[6]"Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway."
Shoham N.G., Centola M., Mansfield E., Hull K.M., Wood G., Wise C.A., Kastner D.L.
Proc. Natl. Acad. Sci. U.S.A. 100:13501-13506(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH MEFV, TISSUE SPECIFICITY, CHARACTERIZATION OF VARIANTS PAPAS THR-230 AND GLN-250, MUTAGENESIS OF TRP-232 AND TYR-345.
[7]"Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants."
Yu J.W., Fernandes-Alnemri T., Datta P., Wu J., Juliana C., Solorzano L., McCormick M., Zhang Z., Alnemri E.S.
Mol. Cell 28:214-227(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBUNIT, INTERACTION WITH MEFV, CHARACTERIZATION OF VARIANTS THR-230 AND GLN-250.
[8]"The PCH family member proline-serine-threonine phosphatase-interacting protein 1 targets to the leukocyte uropod and regulates directed cell migration."
Cooper K.M., Bennin D.A., Huttenlocher A.
Mol. Biol. Cell 19:3180-3191(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH DNM2, SUBCELLULAR LOCATION.
[9]"Identification of SH3 domain interaction partners of human FasL (CD178) by phage display screening."
Voss M., Lettau M., Janssen O.
BMC Immunol. 10:53-53(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH FASLG.
[10]"Pyrin and ASC co-localize to cellular sites that are rich in polymerizing actin."
Waite A.L., Schaner P., Hu C., Richards N., Balci-Peynircioglu B., Hong A., Fox M., Gumucio D.L.
Exp. Biol. Med. (Maywood) 234:40-52(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH MEFV.
[11]"Pyrin Modulates the Intracellular Distribution of PSTPIP1."
Waite A.L., Schaner P., Richards N., Balci-Peynircioglu B., Masters S.L., Brydges S.D., Fox M., Hong A., Yilmaz E., Kastner D.L., Reinherz E.L., Gumucio D.L.
PLoS ONE 4:E6147-E6147(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANTS THR-230 AND LYS-250, MUTAGENESIS OF TRP-232 AND ASP-266.
[12]"Solution structure of the SH3 domain of the human proline-serine-threonine phosphatase-interacting protein 1."
RIKEN structural genomics initiative (RSGI)
Submitted (FEB-2007) to the PDB data bank
Cited for: STRUCTURE BY NMR OF 358-416.
[13]"Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder."
Wise C.A., Gillum J.D., Seidman C.E., Lindor N.M., Veile R., Bashiardes S., Lovett M.
Hum. Mol. Genet. 11:961-969(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS PAPAS THR-230 AND GLN-250, CHARACTERIZATION OF VARIANTS PAPAS THR-230 AND GLN-250.
[14]"Brief report: genotype, phenotype, and clinical course in five patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne)."
Demidowich A.P., Freeman A.F., Kuhns D.B., Aksentijevich I., Gallin J.I., Turner M.L., Kastner D.L., Holland S.M.
Arthritis Rheum. 64:2022-2027(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS PAPAS THR-230; GLN-250 AND LYS-250.
+Additional computationally mapped references.

Web resources

INFEVERS

Repertory of FMF and hereditary autoinflammatory disorders mutations

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF038602 mRNA. Translation: AAD11958.1.
AF038603 mRNA. Translation: AAD11959.1.
U94778 mRNA. Translation: AAD00762.1.
AB451310 mRNA. Translation: BAG70124.1.
AB451440 mRNA. Translation: BAG70254.1.
CH471136 Genomic DNA. Translation: EAW99213.1.
BC008602 mRNA. Translation: AAH08602.1.
CCDSCCDS45312.1. [O43586-1]
RefSeqNP_003969.2. NM_003978.3. [O43586-1]
UniGeneHs.129758.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2DILNMR-A361-416[»]
ProteinModelPortalO43586.
SMRO43586. Positions 9-265, 328-416.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid114513. 35 interactions.
IntActO43586. 5 interactions.
MINTMINT-1130527.
STRING9606.ENSP00000368914.

PTM databases

PhosphoSiteO43586.

Proteomic databases

MaxQBO43586.
PaxDbO43586.
PRIDEO43586.

Protocols and materials databases

DNASU9051.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000558012; ENSP00000452746; ENSG00000140368. [O43586-1]
ENST00000559295; ENSP00000452743; ENSG00000140368. [O43586-2]
GeneID9051.
KEGGhsa:9051.
UCSCuc002bcf.2. human. [O43586-1]
uc010bkw.1. human. [O43586-2]

Organism-specific databases

CTD9051.
GeneCardsGC15P077287.
HGNCHGNC:9580. PSTPIP1.
HPAHPA010600.
MIM604416. phenotype.
606347. gene.
neXtProtNX_O43586.
Orphanet69126. Pyogenic arthritis - pyoderma gangrenosum - acne.
PharmGKBPA33931.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG303711.
HOGENOMHOG000294218.
HOVERGENHBG052960.
InParanoidO43586.
KOK12804.
OMANYYDREV.
PhylomeDBO43586.
TreeFamTF313677.

Enzyme and pathway databases

ReactomeREACT_6900. Immune System.
SignaLinkO43586.

Gene expression databases

ArrayExpressO43586.
BgeeO43586.
CleanExHS_PSTPIP1.
GenevestigatorO43586.

Family and domain databases

InterProIPR001060. FCH_dom.
IPR001452. SH3_domain.
IPR013315. Spectrin_alpha_SH3.
[Graphical view]
PfamPF00611. FCH. 1 hit.
PF14604. SH3_9. 1 hit.
[Graphical view]
PRINTSPR00452. SH3DOMAIN.
PR01887. SPECTRNALPHA.
SMARTSM00055. FCH. 1 hit.
SM00326. SH3. 1 hit.
[Graphical view]
SUPFAMSSF50044. SSF50044. 1 hit.
PROSITEPS50133. FCH. 1 hit.
PS50002. SH3. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceO43586.
GeneWikiPSTPIP1.
GenomeRNAi9051.
NextBio33911.
PROO43586.
SOURCESearch...

Entry information

Entry namePPIP1_HUMAN
AccessionPrimary (citable) accession number: O43586
Secondary accession number(s): B5BU74 expand/collapse secondary AC list , B5BUK4, O43585, O95657
Entry history
Integrated into UniProtKB/Swiss-Prot: September 13, 2005
Last sequence update: June 1, 1998
Last modified: July 9, 2014
This is version 123 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

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

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 15

Human chromosome 15: entries, gene names and cross-references to MIM