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Protein

Xaa-Pro aminopeptidase 3

Gene

XPNPEP3

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

Functioni

Catalyzes the removal of a penultimate prolyl residue from the N-termini of peptides, such as Leu-Pro-Ala (PubMed:25609706, PubMed:28476889). Also shows low activity towards peptides with Ala or Ser at the P1 position (PubMed:28476889).2 Publications
Isoform 1: Promotes TNFRSF1B-mediated phosphorylation of MAPK8/JNK1 and MAPK9/JNK2, suggesting a function as an adapter protein for TNFRSF1B; the effect is independent of XPNPEP3 peptidase activity. May inhibit apoptotic cell death induced via TNF-TNFRSF1B signaling.1 Publication

Catalytic activityi

Release of any N-terminal amino acid, including proline, that is linked to proline, even from a dipeptide or tripeptide.2 Publications

Cofactori

Mn2+1 PublicationNote: Binds 2 manganese ions per subunit.1 Publication

Kineticsi

  1. KM=1.62 mM for Met-Pro-Ala1 Publication
  2. KM=2.45 mM for Leu-Pro-Ala1 Publication
  3. KM=3.06 mM for Phe-Pro-Ala1 Publication
  4. KM=0.55 mM for Tyr-Pro-Ala1 Publication
  5. KM=4.91 mM for Tyr-Ser-Ser1 Publication
  6. KM=4.20 mM for Tyr-Ala-Ala1 Publication
  7. KM=3.74 mM for Tyr-Ser-Ser-Ala-Ala-Ala-Ala1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Binding sitei300SubstrateCombined sources1 Publication1
    Metal bindingi331Manganese 2Combined sources1 Publication1
    Binding sitei331SubstrateCombined sources1 Publication1
    Metal bindingi342Manganese 1Combined sources1 Publication1
    Metal bindingi342Manganese 2Combined sources1 Publication1
    Binding sitei342SubstrateCombined sources1 Publication1 Publication1
    Metal bindingi424Manganese 1Combined sources1 Publication1
    Binding sitei424SubstrateCombined sources1 Publication1
    Binding sitei431SubstrateCombined sources1 Publication1
    Metal bindingi451Manganese 1Combined sources1 Publication1
    Binding sitei451SubstrateCombined sources1 Publication1
    Metal bindingi475Manganese 1Combined sources1 Publication1
    Metal bindingi475Manganese 2Combined sources1 Publication1
    Binding sitei475SubstrateCombined sources1 Publication1 Publication1

    GO - Molecular functioni

    • aminopeptidase activity Source: MGI
    • manganese ion binding Source: InterPro
    • metallopeptidase activity Source: UniProtKB-KW

    GO - Biological processi

    • glomerular filtration Source: MGI
    • protein processing Source: MGI

    Keywordsi

    Molecular functionAminopeptidase, Hydrolase, Metalloprotease, Protease
    LigandManganese, Metal-binding

    Enzyme and pathway databases

    BRENDAi3.4.11.9 2681

    Protein family/group databases

    MEROPSiM24.026

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Xaa-Pro aminopeptidase 3Imported (EC:3.4.11.92 Publications)
    Short name:
    X-Pro aminopeptidase 3
    Alternative name(s):
    Aminopeptidase P3
    Short name:
    APP3
    Gene namesi
    Name:XPNPEP3
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 22

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000196236.12
    HGNCiHGNC:28052 XPNPEP3
    MIMi613553 gene
    neXtProtiNX_Q9NQH7

    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, Mitochondrion

    Pathology & Biotechi

    Involvement in diseasei

    Nephronophthisis-like nephropathy 1 (NPHPL1)1 Publication
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionA disorder with features of nephronophthisis, a cystic kidney disease leading to end-stage renal failure. Nephronophthisis is histologically characterized by modifications of the tubules with thickening of the basement membrane, interstitial fibrosis and, in the advanced stages, medullary cysts. Typical clinical manifestation are chronic renal failure, anemia, polyuria, polydipsia, isosthenuria, and growth retardation. Associations with extrarenal symptoms are frequent. In NPHPL1 patients, extrarenal symptoms include hypertension, essential tremor, sensorineural hearing loss and gout. Severely affected individuals can manifest a mitochondrial disorder with isolated complex I deficiency activity in muscle, seizures, mental retardation and hypertrophic dilated cardiomyopathy.
    See also OMIM:613159
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_063820453G → C in NPHPL1. 1 PublicationCorresponds to variant dbSNP:rs267607179EnsemblClinVar.1

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi18R → A: Prevents cleavage of N-terminal transit peptide; when associated with A-29-30-A; A-39-40-A and A-44. 1 Publication1
    Mutagenesisi29 – 30RR → AA: Prevents cleavage of N-terminal transit peptide; when associated with A-18; A-39-40-A and A-44. 1 Publication2
    Mutagenesisi39 – 40RR → AA: Prevents cleavage of N-terminal transit peptide; when associated with A-18; A-29-30-A and A-44. 1 Publication2
    Mutagenesisi44R → A: Prevents cleavage of N-terminal transit peptide; when associated with A-18; A-29-30-A and A-39-40-A. 1 Publication1
    Mutagenesisi314H → A: Impairs catalytic activity. 1 Publication1
    Mutagenesisi342D → A: Impairs catalytic activity. 1 Publication1
    Mutagenesisi475E → A: Impairs catalytic activity. 1 Publication1

    Keywords - Diseasei

    Disease mutation, Nephronophthisis

    Organism-specific databases

    DisGeNETi63929
    MalaCardsiXPNPEP3
    MIMi613159 phenotype
    OpenTargetsiENSG00000196236
    Orphaneti93589 Late-onset nephronophthisis
    PharmGKBiPA147357130

    Chemistry databases

    ChEMBLiCHEMBL3831223

    Polymorphism and mutation databases

    BioMutaiXPNPEP3
    DMDMi74761652

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Transit peptidei1 – 31MitochondrionSequence analysis1 PublicationAdd BLAST31
    ChainiPRO_000025565432 – 507Xaa-Pro aminopeptidase 3Add BLAST476

    Proteomic databases

    EPDiQ9NQH7
    MaxQBiQ9NQH7
    PaxDbiQ9NQH7
    PeptideAtlasiQ9NQH7
    PRIDEiQ9NQH7

    PTM databases

    iPTMnetiQ9NQH7
    PhosphoSitePlusiQ9NQH7

    Expressioni

    Tissue specificityi

    Isoform 1 and isoform 2 are widely expressed, with isoform 1 being more abundant.1 Publication

    Gene expression databases

    BgeeiENSG00000196236
    CleanExiHS_XPNPEP3
    ExpressionAtlasiQ9NQH7 baseline and differential
    GenevisibleiQ9NQH7 HS

    Organism-specific databases

    HPAiHPA000527

    Interactioni

    Subunit structurei

    Homodimer (PubMed:28476889). Isoform 1 interacts with TNFRSF1B/TNFR2 (activated) and TRAF2 (PubMed:25609706).2 Publications

    Protein-protein interaction databases

    BioGridi121997, 28 interactors
    IntActiQ9NQH7, 11 interactors
    MINTiQ9NQH7
    STRINGi9606.ENSP00000349658

    Structurei

    Secondary structure

    1507
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Beta strandi62 – 64Combined sources3
    Helixi69 – 85Combined sources17
    Beta strandi94 – 100Combined sources7
    Beta strandi106 – 108Combined sources3
    Helixi119 – 125Combined sources7
    Beta strandi133 – 138Combined sources6
    Beta strandi147 – 153Combined sources7
    Helixi158 – 164Combined sources7
    Helixi170 – 177Combined sources8
    Beta strandi180 – 184Combined sources5
    Helixi185 – 191Combined sources7
    Helixi192 – 196Combined sources5
    Beta strandi200 – 203Combined sources4
    Helixi212 – 218Combined sources7
    Helixi220 – 227Combined sources8
    Beta strandi229 – 231Combined sources3
    Helixi237 – 244Combined sources8
    Helixi249 – 271Combined sources23
    Beta strandi275 – 278Combined sources4
    Helixi279 – 292Combined sources14
    Beta strandi297 – 300Combined sources4
    Beta strandi303 – 306Combined sources4
    Helixi307 – 311Combined sources5
    Beta strandi320 – 322Combined sources3
    Beta strandi327 – 332Combined sources6
    Beta strandi334 – 336Combined sources3
    Beta strandi343 – 348Combined sources6
    Helixi355 – 373Combined sources19
    Helixi381 – 398Combined sources18
    Helixi405 – 411Combined sources7
    Helixi412 – 417Combined sources6
    Beta strandi427 – 431Combined sources5
    Beta strandi447 – 450Combined sources4
    Beta strandi453 – 456Combined sources4
    Helixi465 – 467Combined sources3
    Beta strandi470 – 473Combined sources4
    Beta strandi475 – 479Combined sources5
    Beta strandi482 – 484Combined sources3
    Turni488 – 491Combined sources4
    Helixi496 – 502Combined sources7

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    5X49X-ray1.65A/B54-507[»]
    ProteinModelPortaliQ9NQH7
    SMRiQ9NQH7
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni54 – 79Interaction with TNFRSF1B1 PublicationAdd BLAST26

    Sequence similaritiesi

    Belongs to the peptidase M24B family.Curated

    Keywords - Domaini

    Transit peptide

    Phylogenomic databases

    eggNOGiKOG2414 Eukaryota
    COG0006 LUCA
    GeneTreeiENSGT00550000074909
    HOVERGENiHBG057305
    InParanoidiQ9NQH7
    KOiK01262
    OMAiKKYFMHG
    OrthoDBiEOG091G09J7
    PhylomeDBiQ9NQH7
    TreeFamiTF314484

    Family and domain databases

    Gene3Di3.40.350.10, 1 hit
    InterProiView protein in InterPro
    IPR007865 Aminopep_P_N
    IPR029149 Creatin/AminoP/Spt16_NTD
    IPR036005 Creatinase/aminopeptidase-like
    IPR000994 Pept_M24
    PfamiView protein in Pfam
    PF05195 AMP_N, 1 hit
    PF00557 Peptidase_M24, 1 hit
    SMARTiView protein in SMART
    SM01011 AMP_N, 1 hit
    SUPFAMiSSF53092 SSF53092, 1 hit
    SSF55920 SSF55920, 1 hit

    Sequences (5)i

    Sequence statusi: Complete.

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

    This entry describes 5 isoformsi produced by alternative splicing. AlignAdd to basket

    Isoform 1 (identifier: Q9NQH7-1) [UniParc]FASTAAdd to basket
    Also known as: m1 Publication

    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
    MPWLLSAPKL VPAVANVRGL SGCMLCSQRR YSLQPVPERR IPNRYLGQPS
    60 70 80 90 100
    PFTHPHLLRP GEVTPGLSQV EYALRRHKLM SLIQKEAQGQ SGTDQTVVVL
    110 120 130 140 150
    SNPTYYMSND IPYTFHQDNN FLYLCGFQEP DSILVLQSLP GKQLPSHKAI
    160 170 180 190 200
    LFVPRRDPSR ELWDGPRSGT DGAIALTGVD EAYTLEEFQH LLPKMKAETN
    210 220 230 240 250
    MVWYDWMRPS HAQLHSDYMQ PLTEAKAKSK NKVRGVQQLI QRLRLIKSPA
    260 270 280 290 300
    EIERMQIAGK LTSQAFIETM FTSKAPVEEA FLYAKFEFEC RARGADILAY
    310 320 330 340 350
    PPVVAGGNRS NTLHYVKNNQ LIKDGEMVLL DGGCESSCYV SDITRTWPVN
    360 370 380 390 400
    GRFTAPQAEL YEAVLEIQRD CLALCFPGTS LENIYSMMLT LIGQKLKDLG
    410 420 430 440 450
    IMKNIKENNA FKAARKYCPH HVGHYLGMDV HDTPDMPRSL PLQPGMVITI
    460 470 480 490 500
    EPGIYIPEDD KDAPEKFRGL GVRIEDDVVV TQDSPLILSA DCPKEMNDIE

    QICSQAS
    Length:507
    Mass (Da):57,034
    Last modified:October 1, 2000 - v1
    Checksum:i82D886736ABD0B5B
    GO
    Isoform 2 (identifier: Q9NQH7-2) [UniParc]FASTAAdd to basket
    Also known as: c1 Publication

    The sequence of this isoform differs from the canonical sequence as follows:
         1-79: Missing.

    Show »
    Length:428
    Mass (Da):48,112
    Checksum:iE95AFE73A5D94D49
    GO
    Isoform 3 (identifier: Q9NQH7-3) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         265-278: AFIETMFTSKAPVE → RQGFSVLSRLVSNS
         279-507: Missing.

    Note: No experimental confirmation available.
    Show »
    Length:278
    Mass (Da):31,529
    Checksum:iB4AD5CEB13853823
    GO
    Isoform 4 (identifier: Q9NQH7-4) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-23: Missing.

    Note: No experimental confirmation available.
    Show »
    Length:484
    Mass (Da):54,672
    Checksum:i6320B2E5975918BB
    GO
    Isoform 5 (identifier: Q9NQH7-5) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         265-288: AFIETMFTSKAPVEEAFLYAKFEF → KSVLLARHGGSRLYSHHFGRPRLS
         289-507: Missing.

    Note: No experimental confirmation available.
    Show »
    Length:288
    Mass (Da):32,712
    Checksum:iE245C092422567ED
    GO

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti340V → A in CAG33677 (Ref. 1) Curated1
    Sequence conflicti486L → F in AAH01681 (PubMed:15489334).Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_051573450I → L. Corresponds to variant dbSNP:rs17002243Ensembl.1
    Natural variantiVAR_063820453G → C in NPHPL1. 1 PublicationCorresponds to variant dbSNP:rs267607179EnsemblClinVar.1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_0212961 – 79Missing in isoform 2. 1 PublicationAdd BLAST79
    Alternative sequenceiVSP_0401421 – 23Missing in isoform 4. 1 PublicationAdd BLAST23
    Alternative sequenceiVSP_040143265 – 288AFIET…AKFEF → KSVLLARHGGSRLYSHHFGR PRLS in isoform 5. 1 PublicationAdd BLAST24
    Alternative sequenceiVSP_021297265 – 278AFIET…KAPVE → RQGFSVLSRLVSNS in isoform 3. 1 PublicationAdd BLAST14
    Alternative sequenceiVSP_021298279 – 507Missing in isoform 3. 1 PublicationAdd BLAST229
    Alternative sequenceiVSP_040144289 – 507Missing in isoform 5. 1 PublicationAdd BLAST219

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    CR457396 mRNA Translation: CAG33677.1
    AL365514 mRNA Translation: CAB97210.1
    CR456442 mRNA Translation: CAG30328.1
    AK301635 mRNA Translation: BAH13526.1
    AK301758 mRNA Translation: BAH13548.1
    AK313770 mRNA Translation: BAG36508.1
    AL834310 mRNA Translation: CAD38980.1
    AL035450 Genomic DNA No translation available.
    Z98048 Genomic DNA No translation available.
    CH471095 Genomic DNA Translation: EAW60399.1
    BC001208 mRNA Translation: AAH01208.1
    BC001681 mRNA Translation: AAH01681.1
    BC004989 mRNA Translation: AAH04989.1
    CCDSiCCDS14007.1 [Q9NQH7-1]
    RefSeqiNP_071381.1, NM_022098.3 [Q9NQH7-1]
    UniGeneiHs.529163

    Genome annotation databases

    EnsembliENST00000357137; ENSP00000349658; ENSG00000196236 [Q9NQH7-1]
    GeneIDi63929
    KEGGihsa:63929
    UCSCiuc003azh.4 human [Q9NQH7-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Similar proteinsi

    Entry informationi

    Entry nameiXPP3_HUMAN
    AccessioniPrimary (citable) accession number: Q9NQH7
    Secondary accession number(s): B2R9G1
    , B7Z790, B7Z7B2, Q6I9V9, Q8NDA6, Q9BV27, Q9BVH0
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 31, 2006
    Last sequence update: October 1, 2000
    Last modified: May 23, 2018
    This is version 154 of the entry and version 1 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 22
      Human chromosome 22: 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. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. Peptidase families
      Classification of peptidase families and list of entries
    7. SIMILARITY comments
      Index of protein domains and families

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