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Protein

Nuclear inhibitor of protein phosphatase 1

Gene

PPP1R8

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

Functioni

Inhibitor subunit of the major nuclear protein phosphatase-1 (PP-1). It has RNA-binding activity but does not cleave RNA and may target PP-1 to RNA-associated substrates. May also be involved in pre-mRNA splicing. Binds DNA and might act as a transcriptional repressor. Seems to be required for cell proliferation.
Isoform Gamma is a site-specific single-strand endoribonuclease that cleaves single strand RNA 3' to purines and pyrimidines in A+U-rich regions. It generates 5'-phosphate termini at the site of cleavage. This isoform does not inhibit PP-1. May be implicated in mRNA splicing.

Miscellaneous

A synthetic peptide, NIPP-1(330-351), is able to inhibit PP-1. Phosphorylation of Tyr-335 reduces PP-1 inhibition, whereas phosphorylation of Thr-346 or Ser-348 has no effect.

Cofactori

Mg2+Note: Endoribonuclease function is magnesium-dependent.

GO - Molecular functioni

  • DNA binding Source: UniProtKB-KW
  • endonuclease activity Source: UniProtKB-KW
  • mRNA binding Source: GO_Central
  • protein serine/threonine phosphatase inhibitor activity Source: ProtInc
  • ribonuclease E activity Source: ProtInc
  • RNA binding Source: ProtInc

GO - Biological processi

Keywordsi

Molecular functionDNA-binding, Endonuclease, Hydrolase, Nuclease, Protein phosphatase inhibitor, Repressor, RNA-binding
Biological processmRNA processing, mRNA splicing, Transcription, Transcription regulation
LigandMagnesium

Enzyme and pathway databases

SIGNORiQ12972.

Names & Taxonomyi

Protein namesi
Recommended name:
Nuclear inhibitor of protein phosphatase 1
Short name:
NIPP-1
Alternative name(s):
Protein phosphatase 1 regulatory inhibitor subunit 8
Including the following 1 domains:
Activator of RNA decay (EC:3.1.4.-)
Alternative name(s):
ARD-1
Gene namesi
Name:PPP1R8
Synonyms:ARD1, NIPP1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

EuPathDBiHostDB:ENSG00000117751.17.
HGNCiHGNC:9296. PPP1R8.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus, Spliceosome

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi68 – 71SRVH → AAAA: Abolishes interaction with CDC5L, SF3B1 and MELK, and localization in nuclear speckles. No effect on repressor activity. 5 Publications4
Mutagenesisi193 – 197KRKRK → AAAAA: No effect on interaction with EED. 1 Publication5
Mutagenesisi195 – 197KRK → AAA: Abolishes nuclear import; when associated with A-234--237-A. 1 Publication3
Mutagenesisi199S → A or D: No change in subcellular location, no effect on interaction with EED or repressor activity; when associated with A-204 or D-204. 2 Publications1
Mutagenesisi201V → A: Reduces PP-1 binding, no effect on subcellular location or repressor activity and prevents retargeting of PPP1CA and PPP1CC to nuclear speckles; when associated with A-203. 3 Publications1
Mutagenesisi203F → A: Reduces PP-1 binding, no effect on subcellular location or repressor activity and prevents retargeting of PPP1CA and PPP1CC to nuclear speckles; when associated with A-201. 3 Publications1
Mutagenesisi204S → A or D: No change in subcellular location, no effect on interaction with EED or repressor activity; when associated with A-199 or D-199. 2 Publications1
Mutagenesisi234 – 237KKKR → AAAA: Abolishes nuclear import; when associated with A-195-197-A. 1 Publication4
Mutagenesisi264Y → D: Abolishes in vitro phosphorylation of isoform gamma by Lyn. 1 Publication1
Mutagenesisi335Y → D: Decreases the ability of isoform Gamma to bind and inhibit PP-1. 1 Publication1
Mutagenesisi346T → D: No effect on the ability of isoform Gamma to inhibit PP-1. 1 Publication1
Mutagenesisi348S → D: No effect on the ability of isoform Gamma to inhibit PP-1. 1 Publication1

Organism-specific databases

DisGeNETi5511.
OpenTargetsiENSG00000117751.
PharmGKBiPA33659.

Polymorphism and mutation databases

BioMutaiPPP1R8.
DMDMi19863082.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000715051 – 351Nuclear inhibitor of protein phosphatase 1Add BLAST351

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei161PhosphothreonineBy similarity1
Modified residuei178PhosphoserineBy similarity1
Modified residuei199PhosphoserineBy similarity1
Modified residuei249PhosphoserineCombined sources1
Modified residuei264Phosphotyrosine; by LYN; in vitro1 Publication1
Modified residuei335Phosphotyrosine1 Publication1

Post-translational modificationi

May be inactivated by phosphorylation on Ser-199 or Ser-204 (By similarity). Phosphorylated by Lyn in vitro on Tyr-264, and also on Tyr-335 in the presence of RNA.By similarity1 Publication

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ12972.
PaxDbiQ12972.
PeptideAtlasiQ12972.
PRIDEiQ12972.

PTM databases

iPTMnetiQ12972.
PhosphoSitePlusiQ12972.

Expressioni

Tissue specificityi

Ubiquitously expressed, with highest levels in heart and skeletal muscle, followed by brain, placenta, lung, liver and pancreas. Less abundant in kidney. The concentration and ratio between isoforms is cell-type dependent. Isoform Alpha (>90%) and isoform Beta were found in brain, heart and kidney. Isoform Gamma is mainly found in B-cells and T-lymphocytes, and has been found in 293 embryonic kidney cells.2 Publications

Gene expression databases

BgeeiENSG00000117751.
CleanExiHS_PPP1R8.
ExpressionAtlasiQ12972. baseline and differential.
GenevisibleiQ12972. HS.

Organism-specific databases

HPAiHPA027406.
HPA027417.
HPA027452.

Interactioni

Subunit structurei

Interacts with phosphorylated CDC5L, SF3B1 and MELK. Interacts with EED, in a nucleic acid-stimulated manner. Part of a complex consisting of PPP1R8, EED, HDAC2 and PP-1. Part of the spliceosome. Interacts with PPP1CA, PPP1CB and PPP1CC.6 Publications

Binary interactionsi

Show more details

Protein-protein interaction databases

BioGridi111503. 45 interactors.
DIPiDIP-40815N.
ELMiQ12972.
IntActiQ12972. 20 interactors.
MINTiMINT-133673.
STRINGi9606.ENSP00000311677.

Structurei

Secondary structure

1351
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi162 – 174Combined sources13
Beta strandi208 – 210Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3V4YX-ray2.10B/D/F/H158-216[»]
DisProtiDP00937.
ProteinModelPortaliQ12972.
SMRiQ12972.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini49 – 101FHAPROSITE-ProRule annotationAdd BLAST53

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 142Interaction with CDC5L, SF3B1 and MELK3 PublicationsAdd BLAST142
Regioni143 – 224Interaction with EED1 PublicationAdd BLAST82
Regioni191 – 200Involved in PP-1 inhibition10
Regioni200 – 203Involved in PP-1 binding4
Regioni310 – 329Interaction with EED1 PublicationAdd BLAST20
Regioni330 – 351RNA-bindingAdd BLAST22
Regioni331 – 337Involved in PP-1 inhibition7

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi185 – 209Nuclear localization signal 11 PublicationAdd BLAST25
Motifi210 – 240Nuclear localization signal 21 PublicationAdd BLAST31

Domaini

Has a basic N- and C-terminal and an acidic central domain.
The FHA domain mediates interactions with threonine-phosphorylated MELK.By similarity

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG1880. Eukaryota.
ENOG410XTHZ. LUCA.
GeneTreeiENSGT00730000110659.
HOGENOMiHOG000231315.
HOVERGENiHBG053645.
InParanoidiQ12972.
KOiK13216.
OMAiDEKRCYL.
OrthoDBiEOG091G0D26.
PhylomeDBiQ12972.
TreeFamiTF105539.

Family and domain databases

CDDicd00060. FHA. 1 hit.
InterProiView protein in InterPro
IPR000253. FHA_dom.
IPR008984. SMAD_FHA_dom_sf.
PfamiView protein in Pfam
PF00498. FHA. 1 hit.
SMARTiView protein in SMART
SM00240. FHA. 1 hit.
SUPFAMiSSF49879. SSF49879. 1 hit.
PROSITEiView protein in PROSITE
PS50006. FHA_DOMAIN. 1 hit.

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform Alpha (identifier: Q12972-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MAAAANSGSS LPLFDCPTWA GKPPPGLHLD VVKGDKLIEK LIIDEKKYYL
60 70 80 90 100
FGRNPDLCDF TIDHQSCSRV HAALVYHKHL KRVFLIDLNS THGTFLGHIR
110 120 130 140 150
LEPHKPQQIP IDSTVSFGAS TRAYTLREKP QTLPSAVKGD EKMGGEDDEL
160 170 180 190 200
KGLLGLPEEE TELDNLTEFN TAHNKRISTL TIEEGNLDIQ RPKRKRKNSR
210 220 230 240 250
VTFSEDDEII NPEDVDPSVG RFRNMVQTAV VPVKKKRVEG PGSLGLEESG
260 270 280 290 300
SRRMQNFAFS GGLYGGLPPT HSEAGSQPHG IHGTALIGGL PMPYPNLAPD
310 320 330 340 350
VDLTPVVPSA VNMNPAPNPA VYNPEAVNEP KKKKYAKEAW PGKKPTPSLL

I
Length:351
Mass (Da):38,479
Last modified:December 1, 2000 - v2
Checksum:i0A0E92B033E37641
GO
Isoform Beta (identifier: Q12972-2) [UniParc]FASTAAdd to basket
Also known as: Delta

The sequence of this isoform differs from the canonical sequence as follows:
     1-142: Missing.

Show »
Length:209
Mass (Da):22,711
Checksum:iB8A896191A4AB026
GO
Isoform Gamma (identifier: Q12972-3) [UniParc]FASTAAdd to basket
Also known as: ARD-1

The sequence of this isoform differs from the canonical sequence as follows:
     1-224: Missing.

Show »
Length:127
Mass (Da):13,344
Checksum:iD29E123EA36C9F94
GO

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0051201 – 224Missing in isoform Gamma. 1 PublicationAdd BLAST224
Alternative sequenceiVSP_0051191 – 142Missing in isoform Beta. 2 PublicationsAdd BLAST142

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U14575 mRNA. Translation: AAA64749.1.
AF061958 mRNA. Translation: AAD31541.1.
AF061959 mRNA. Translation: AAD31542.1.
AF064757
, AF064751, AF064752, AF064753, AF064754, AF064755, AF064756 Genomic DNA. Translation: AAD24669.1.
AF064757
, AF064754, AF064755, AF064756 Genomic DNA. Translation: AAD24670.1.
AF126488 mRNA. Translation: AAD22486.1.
AK292077 mRNA. Translation: BAF84766.1.
AL020997 Genomic DNA. No translation available.
AL109927 Genomic DNA. No translation available.
CH471059 Genomic DNA. Translation: EAX07731.1.
CH471059 Genomic DNA. Translation: EAX07732.1.
BC001597 mRNA. Translation: AAH01597.1.
BC013360 mRNA. Translation: AAH13360.1.
CCDSiCCDS311.1. [Q12972-1]
CCDS312.1. [Q12972-2]
CCDS313.1. [Q12972-3]
PIRiI38856.
RefSeqiNP_002704.1. NM_002713.3. [Q12972-3]
NP_054829.2. NM_014110.4. [Q12972-1]
NP_612568.1. NM_138558.2. [Q12972-2]
XP_016857083.1. XM_017001594.1. [Q12972-3]
UniGeneiHs.533474.

Genome annotation databases

EnsembliENST00000236412; ENSP00000236412; ENSG00000117751. [Q12972-3]
ENST00000311772; ENSP00000311677; ENSG00000117751. [Q12972-1]
ENST00000373931; ENSP00000363042; ENSG00000117751. [Q12972-2]
GeneIDi5511.
KEGGihsa:5511.
UCSCiuc001bov.3. human. [Q12972-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiPP1R8_HUMAN
AccessioniPrimary (citable) accession number: Q12972
Secondary accession number(s): Q5TEJ2
, Q5TEJ4, Q5TIF2, Q6PKF6, Q9UBH1, Q9UBZ0
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: December 1, 2000
Last modified: November 22, 2017
This is version 172 of the entry and version 2 of the sequence. See 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

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references