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O14773

- TPP1_HUMAN

UniProt

O14773 - TPP1_HUMAN

Protein

Tripeptidyl-peptidase 1

Gene

TPP1

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 156 (01 Oct 2014)
      Sequence version 2 (30 May 2006)
      Previous versions | rss
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    Functioni

    Lysosomal serine protease with tripeptidyl-peptidase I activity. May act as a non-specific lysosomal peptidase which generates tripeptides from the breakdown products produced by lysosomal proteinases. Requires substrates with an unsubstituted N-terminus By similarity.By similarity

    Catalytic activityi

    Release of an N-terminal tripeptide from a polypeptide, but also has endopeptidase activity.

    Cofactori

    Binds 1 calcium ion per subunit.

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Active sitei272 – 2721Charge relay system
    Active sitei276 – 2761Charge relay system
    Active sitei475 – 4751Charge relay system
    Metal bindingi517 – 5171Calcium
    Metal bindingi518 – 5181Calcium; via carbonyl oxygen
    Metal bindingi539 – 5391Calcium; via carbonyl oxygen
    Metal bindingi541 – 5411Calcium; via carbonyl oxygen
    Metal bindingi543 – 5431Calcium

    GO - Molecular functioni

    1. endopeptidase activity Source: UniProtKB
    2. metal ion binding Source: UniProtKB-KW
    3. peptidase activity Source: UniProtKB
    4. peptide binding Source: UniProtKB
    5. protein binding Source: UniProtKB
    6. serine-type endopeptidase activity Source: InterPro
    7. serine-type peptidase activity Source: UniProtKB
    8. tripeptidyl-peptidase activity Source: UniProtKB

    GO - Biological processi

    1. activation of signaling protein activity involved in unfolded protein response Source: Reactome
    2. bone resorption Source: UniProtKB
    3. cell death Source: UniProtKB-KW
    4. cellular protein metabolic process Source: Reactome
    5. endoplasmic reticulum unfolded protein response Source: Reactome
    6. epithelial cell differentiation Source: UniProt
    7. lipid metabolic process Source: ProtInc
    8. lysosome organization Source: UniProtKB
    9. nervous system development Source: UniProtKB
    10. neuromuscular process controlling balance Source: UniProtKB
    11. peptide catabolic process Source: UniProtKB
    12. protein catabolic process Source: UniProtKB
    13. proteolysis Source: UniProtKB

    Keywords - Molecular functioni

    Hydrolase, Protease, Serine protease

    Keywords - Ligandi

    Calcium, Metal-binding

    Enzyme and pathway databases

    BRENDAi3.4.14.9. 2681.
    ReactomeiREACT_18273. XBP1(S) activates chaperone genes.
    SABIO-RKO14773.
    SignaLinkiO14773.

    Protein family/group databases

    MEROPSiS53.003.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Tripeptidyl-peptidase 1 (EC:3.4.14.9)
    Short name:
    TPP-1
    Alternative name(s):
    Cell growth-inhibiting gene 1 protein
    Lysosomal pepstatin-insensitive protease
    Short name:
    LPIC
    Tripeptidyl aminopeptidase
    Tripeptidyl-peptidase I
    Short name:
    TPP-I
    Gene namesi
    Name:TPP1
    Synonyms:CLN2
    ORF Names:GIG1, UNQ267/PRO304
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 11

    Organism-specific databases

    HGNCiHGNC:2073. TPP1.

    Subcellular locationi

    Lysosome. Melanosome
    Note: Identified by mass spectrometry in melanosome fractions from stage I to stage IV.

    GO - Cellular componenti

    1. extracellular vesicular exosome Source: UniProt
    2. lysosomal lumen Source: Reactome
    3. lysosome Source: UniProtKB
    4. melanosome Source: UniProtKB-SubCell
    5. mitochondrion Source: Ensembl

    Keywords - Cellular componenti

    Lysosome

    Pathology & Biotechi

    Involvement in diseasei

    Ceroid lipofuscinosis, neuronal, 2 (CLN2) [MIM:204500]: A form of neuronal ceroid lipofuscinosis. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material, and clinically by seizures, dementia, visual loss, and/or cerebral atrophy. The lipopigment pattern seen most often in CLN2 consists of curvilinear profiles.12 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti62 – 621S → T in CLN2. 1 Publication
    VAR_066883
    Natural varianti77 – 771G → R in CLN2; displays very low residual enzyme activity; altered intracellular trafficking. 1 Publication
    Corresponds to variant rs121908195 [ dbSNP | Ensembl ].
    VAR_009603
    Natural varianti127 – 1271R → Q in CLN2; displays residual enzyme activity; effectively transported to the lysosome. 2 Publications
    Corresponds to variant rs121908204 [ dbSNP | Ensembl ].
    VAR_016790
    Natural varianti153 – 1531S → P in CLN2.
    VAR_016791
    Natural varianti202 – 2021P → L in CLN2; displays no residual enzyme activity; altered intracellular trafficking. 1 Publication
    Corresponds to variant rs121908205 [ dbSNP | Ensembl ].
    VAR_063640
    Natural varianti206 – 2061R → C in CLN2; displays no residual enzyme activity; altered intracellular trafficking. 1 Publication
    Corresponds to variant rs28940573 [ dbSNP | Ensembl ].
    VAR_009605
    Natural varianti206 – 2061R → H in CLN2. 1 Publication
    Corresponds to variant rs121908209 [ dbSNP | Ensembl ].
    VAR_016792
    Natural varianti209 – 2091Y → H in CLN2. 1 Publication
    VAR_066884
    Natural varianti266 – 2661R → Q in CLN2. 1 Publication
    VAR_066885
    Natural varianti277 – 2771V → M in CLN2; displays no residual enzyme activity; altered intracellular trafficking; demonstrates enhanced processing in response to folding improvement treatment. 1 Publication
    Corresponds to variant rs121908207 [ dbSNP | Ensembl ].
    VAR_016793
    Natural varianti278 – 2781Q → P in CLN2. 1 Publication
    VAR_016794
    Natural varianti284 – 2841G → V in CLN2; displays no residual enzyme activity; altered intracellular trafficking. 2 Publications
    Corresponds to variant rs119455957 [ dbSNP | Ensembl ].
    VAR_016795
    Natural varianti286 – 2861N → S in CLN2; enzymatically inactive; lacks one oligosaccharide chain resulting in enzymatic inactivation and possibly prelysosomal protein degradation; altered intracellular trafficking. 1 Publication
    Corresponds to variant rs119455958 [ dbSNP | Ensembl ].
    VAR_016796
    Natural varianti287 – 2871I → N in CLN2; displays no residual enzyme activity; altered intracellular trafficking. 1 Publication
    Corresponds to variant rs121908196 [ dbSNP | Ensembl ].
    VAR_009606
    Natural varianti339 – 3391R → Q in CLN2. 1 Publication
    VAR_066886
    Natural varianti343 – 3431E → K in CLN2; displays no residual enzyme activity; altered intracellular trafficking. 1 Publication
    Corresponds to variant rs121908197 [ dbSNP | Ensembl ].
    VAR_009607
    Natural varianti353 – 3531T → P in CLN2. 1 Publication
    Corresponds to variant rs121908206 [ dbSNP | Ensembl ].
    VAR_016797
    Natural varianti365 – 3651C → R in CLN2; displays no residual enzyme activity; altered intracellular trafficking. 2 Publications
    Corresponds to variant rs119455953 [ dbSNP | Ensembl ].
    VAR_005643
    Natural varianti365 – 3651C → Y in CLN2. 2 Publications
    Corresponds to variant rs119455954 [ dbSNP | Ensembl ].
    VAR_005644
    Natural varianti382 – 3821S → R in CLN2. 1 Publication
    VAR_066887
    Natural varianti385 – 3851V → D in CLN2. 1 Publication
    Corresponds to variant rs121908198 [ dbSNP | Ensembl ].
    VAR_009608
    Natural varianti389 – 3891G → E in CLN2. 1 Publication
    Corresponds to variant rs121908199 [ dbSNP | Ensembl ].
    VAR_009609
    Natural varianti422 – 4221Q → H in CLN2; displays no residual enzyme activity; altered intracellular trafficking. 1 Publication
    Corresponds to variant rs121908200 [ dbSNP | Ensembl ].
    VAR_009610
    Natural varianti428 – 4281K → N in CLN2. 1 Publication
    VAR_016798
    Natural varianti447 – 4471R → H in CLN2; displays very low residual enzyme activity; altered intracellular trafficking; demonstrates enhanced processing in response to folding improvement treatment; shows a five fold increase under permissive temperature conditions. 1 Publication
    Corresponds to variant rs119455956 [ dbSNP | Ensembl ].
    VAR_005645
    Natural varianti448 – 4481A → V in CLN2. 1 Publication
    VAR_066888
    Natural varianti454 – 4541A → E in CLN2. 1 Publication
    Corresponds to variant rs121908201 [ dbSNP | Ensembl ].
    VAR_009611
    Natural varianti473 – 4731G → R in CLN2. 2 Publications
    Corresponds to variant rs121908203 [ dbSNP | Ensembl ].
    VAR_016799
    Natural varianti475 – 4751S → L in CLN2; displays no residual enzyme activity; effectively transported to the lysosome. 1 Publication
    Corresponds to variant rs121908202 [ dbSNP | Ensembl ].
    VAR_009612
    Natural varianti481 – 4811F → C in CLN2. 1 Publication
    VAR_016800
    Natural varianti482 – 4821G → R in CLN2. 1 Publication
    Corresponds to variant rs121908208 [ dbSNP | Ensembl ].
    VAR_058435
    Natural varianti501 – 5011G → C in CLN2. 1 Publication
    VAR_066889
    Natural varianti504 – 5041N → Y in CLN2. 1 Publication
    VAR_066890
    Natural varianti544 – 5441P → S in CLN2; displays residual enzyme activity; effectively transported to the lysosome. 1 Publication
    Corresponds to variant rs121908210 [ dbSNP | Ensembl ].
    VAR_063641
    Natural varianti548 – 5481W → R in CLN2. 1 Publication
    VAR_066891
    Spinocerebellar ataxia, autosomal recessive, 7 (SCAR7) [MIM:609270]: Spinocerebellar ataxia defines a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR7 patients show difficulty walking and writing, dysarthria, limb ataxia, and cerebellar atrophy.1 Publication
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti466 – 4661V → G in SCAR7. 1 Publication
    VAR_070917

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi236 – 2361H → A: No effect. 1 Publication
    Mutagenesisi360 – 3601D → A: Inactive. Impaired processing. 1 Publication
    Mutagenesisi475 – 4751S → A: Inactive. Impaired processing. 1 Publication
    Mutagenesisi517 – 5171D → A: Inactive. Impaired processing. 1 Publication

    Keywords - Diseasei

    Disease mutation, Epilepsy, Neurodegeneration, Neuronal ceroid lipofuscinosis, Spinocerebellar ataxia

    Organism-specific databases

    MIMi204500. phenotype.
    609270. phenotype.
    Orphaneti284324. Childhood-onset autosomal recessive slowly progressive spinocerebellar ataxia.
    228349. CLN2 disease.
    PharmGKBiPA26600.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Signal peptidei1 – 19191 PublicationAdd
    BLAST
    Propeptidei20 – 195176Removed in mature form1 PublicationPRO_0000027374Add
    BLAST
    Chaini196 – 563368Tripeptidyl-peptidase 1PRO_0000027375Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Disulfide bondi111 ↔ 122
    Glycosylationi210 – 2101N-linked (GlcNAc...)3 Publications
    Glycosylationi222 – 2221N-linked (GlcNAc...)1 Publication
    Glycosylationi286 – 2861N-linked (GlcNAc...)2 Publications
    Glycosylationi313 – 3131N-linked (GlcNAc...)3 Publications
    Disulfide bondi365 ↔ 526
    Glycosylationi443 – 4431N-linked (GlcNAc...)4 Publications
    Disulfide bondi522 ↔ 537

    Post-translational modificationi

    Activated by autocatalytic proteolytical processing upon acidification. N-glycosylation is required for processing and activity.4 Publications

    Keywords - PTMi

    Autocatalytic cleavage, Disulfide bond, Glycoprotein, Zymogen

    Proteomic databases

    MaxQBiO14773.
    PaxDbiO14773.
    PRIDEiO14773.

    PTM databases

    PhosphoSiteiO14773.

    Miscellaneous databases

    PMAP-CutDBO14773.

    Expressioni

    Tissue specificityi

    Detected in all tissues examined with highest levels in heart and placenta and relatively similar levels in other tissues.

    Gene expression databases

    ArrayExpressiO14773.
    BgeeiO14773.
    CleanExiHS_TPP1.
    GenevestigatoriO14773.

    Organism-specific databases

    HPAiHPA037709.

    Interactioni

    Subunit structurei

    Monomer.1 Publication

    Protein-protein interaction databases

    BioGridi107611. 8 interactions.
    DIPiDIP-47434N.
    IntActiO14773. 18 interactions.
    MINTiMINT-5002180.
    STRINGi9606.ENSP00000299427.

    Structurei

    Secondary structure

    1
    563
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi35 – 406
    Beta strandi46 – 538
    Helixi58 – 6912
    Turni74 – 774
    Helixi82 – 898
    Helixi93 – 10614
    Beta strandi109 – 1135
    Beta strandi119 – 1257
    Helixi126 – 1327
    Beta strandi139 – 1435
    Turni144 – 1474
    Beta strandi148 – 1525
    Helixi161 – 1633
    Turni164 – 1663
    Beta strandi167 – 1704
    Helixi202 – 2087
    Beta strandi219 – 2213
    Beta strandi224 – 2296
    Helixi237 – 24711
    Beta strandi258 – 2625
    Helixi271 – 28313
    Turni284 – 2863
    Beta strandi287 – 2926
    Turni295 – 3006
    Helixi303 – 3119
    Beta strandi319 – 3246
    Helixi329 – 3313
    Helixi334 – 34916
    Beta strandi353 – 3575
    Beta strandi366 – 3683
    Beta strandi371 – 3733
    Turni379 – 3813
    Beta strandi385 – 39713
    Beta strandi402 – 4043
    Beta strandi411 – 4177
    Helixi420 – 4223
    Helixi423 – 43210
    Helixi439 – 4413
    Beta strandi446 – 4494
    Beta strandi451 – 4555
    Beta strandi457 – 4637
    Beta strandi466 – 4716
    Helixi474 – 49421
    Helixi504 – 5096
    Turni510 – 5145
    Beta strandi522 – 5254
    Turni529 – 5335
    Beta strandi534 – 5374
    Turni544 – 5463
    Helixi553 – 5586

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1R60model-A196-563[»]
    3EDYX-ray1.85A20-563[»]
    3EE6X-ray2.35A/B1-563[»]
    ProteinModelPortaliO14773.
    SMRiO14773. Positions 20-563.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiO14773.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini199 – 563365Peptidase S53Add
    BLAST

    Sequence similaritiesi

    Contains 1 peptidase S53 domain.Curated

    Keywords - Domaini

    Signal

    Phylogenomic databases

    eggNOGiCOG4934.
    HOGENOMiHOG000171253.
    HOVERGENiHBG004449.
    InParanoidiO14773.
    KOiK01279.
    OMAiCRVRSAR.
    OrthoDBiEOG7RNJZW.
    PhylomeDBiO14773.
    TreeFamiTF333497.

    Family and domain databases

    Gene3Di3.40.50.200. 1 hit.
    InterProiIPR015366. Peptidase_S53_propep.
    IPR000209. Peptidase_S8/S53_dom.
    IPR009020. Prot_inh_propept.
    [Graphical view]
    PfamiPF00082. Peptidase_S8. 1 hit.
    PF09286. Pro-kuma_activ. 1 hit.
    [Graphical view]
    SMARTiSM00944. Pro-kuma_activ. 1 hit.
    [Graphical view]
    SUPFAMiSSF52743. SSF52743. 1 hit.
    SSF54897. SSF54897. 1 hit.
    PROSITEiPS51695. SEDOLISIN. 1 hit.
    [Graphical view]

    Sequences (2)i

    Sequence statusi: Complete.

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

    This entry describes 2 isoformsi produced by alternative splicing. Align

    Isoform 1 (identifier: O14773-1) [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

    MGLQACLLGL FALILSGKCS YSPEPDQRRT LPPGWVSLGR ADPEEELSLT    50
    FALRQQNVER LSELVQAVSD PSSPQYGKYL TLENVADLVR PSPLTLHTVQ 100
    KWLLAAGAQK CHSVITQDFL TCWLSIRQAE LLLPGAEFHH YVGGPTETHV 150
    VRSPHPYQLP QALAPHVDFV GGLHRFPPTS SLRQRPEPQV TGTVGLHLGV 200
    TPSVIRKRYN LTSQDVGSGT SNNSQACAQF LEQYFHDSDL AQFMRLFGGN 250
    FAHQASVARV VGQQGRGRAG IEASLDVQYL MSAGANISTW VYSSPGRHEG 300
    QEPFLQWLML LSNESALPHV HTVSYGDDED SLSSAYIQRV NTELMKAAAR 350
    GLTLLFASGD SGAGCWSVSG RHQFRPTFPA SSPYVTTVGG TSFQEPFLIT 400
    NEIVDYISGG GFSNVFPRPS YQEEAVTKFL SSSPHLPPSS YFNASGRAYP 450
    DVAALSDGYW VVSNRVPIPW VSGTSASTPV FGGILSLINE HRILSGRPPL 500
    GFLNPRLYQQ HGAGLFDVTR GCHESCLDEE VEGQGFCSGP GWDPVTGWGT 550
    PNFPALLKTL LNP 563
    Length:563
    Mass (Da):61,248
    Last modified:May 30, 2006 - v2
    Checksum:i7299D902F6AE8555
    GO
    Isoform 2 (identifier: O14773-2) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-243: Missing.

    Note: No experimental confirmation available.

    Show »
    Length:320
    Mass (Da):34,464
    Checksum:i707AE6D4A90B0FBC
    GO

    Sequence cautioni

    The sequence AAM08412.1 differs from that shown. Reason: Incorrectly indicated as originating from bovine.
    The sequence AAQ88866.1 differs from that shown. Reason: Frameshift at position 551.

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti115 – 1151I → N in BAD96219. 1 PublicationCurated
    Sequence conflicti373 – 3731Q → E in AAH14863. (PubMed:15489334)Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti62 – 621S → L.
    Corresponds to variant rs2734715 [ dbSNP | Ensembl ].
    VAR_037572
    Natural varianti62 – 621S → T in CLN2. 1 Publication
    VAR_066883
    Natural varianti77 – 771G → R in CLN2; displays very low residual enzyme activity; altered intracellular trafficking. 1 Publication
    Corresponds to variant rs121908195 [ dbSNP | Ensembl ].
    VAR_009603
    Natural varianti100 – 1001Q → R.1 Publication
    Corresponds to variant rs1800746 [ dbSNP | Ensembl ].
    VAR_009604
    Natural varianti127 – 1271R → Q in CLN2; displays residual enzyme activity; effectively transported to the lysosome. 2 Publications
    Corresponds to variant rs121908204 [ dbSNP | Ensembl ].
    VAR_016790
    Natural varianti153 – 1531S → P in CLN2.
    VAR_016791
    Natural varianti175 – 1751R → H.1 Publication
    VAR_005642
    Natural varianti185 – 1851R → C.
    Corresponds to variant rs34758634 [ dbSNP | Ensembl ].
    VAR_037573
    Natural varianti202 – 2021P → L in CLN2; displays no residual enzyme activity; altered intracellular trafficking. 1 Publication
    Corresponds to variant rs121908205 [ dbSNP | Ensembl ].
    VAR_063640
    Natural varianti206 – 2061R → C in CLN2; displays no residual enzyme activity; altered intracellular trafficking. 1 Publication
    Corresponds to variant rs28940573 [ dbSNP | Ensembl ].
    VAR_009605
    Natural varianti206 – 2061R → H in CLN2. 1 Publication
    Corresponds to variant rs121908209 [ dbSNP | Ensembl ].
    VAR_016792
    Natural varianti209 – 2091Y → H in CLN2. 1 Publication
    VAR_066884
    Natural varianti266 – 2661R → Q in CLN2. 1 Publication
    VAR_066885
    Natural varianti277 – 2771V → M in CLN2; displays no residual enzyme activity; altered intracellular trafficking; demonstrates enhanced processing in response to folding improvement treatment. 1 Publication
    Corresponds to variant rs121908207 [ dbSNP | Ensembl ].
    VAR_016793
    Natural varianti278 – 2781Q → P in CLN2. 1 Publication
    VAR_016794
    Natural varianti284 – 2841G → V in CLN2; displays no residual enzyme activity; altered intracellular trafficking. 2 Publications
    Corresponds to variant rs119455957 [ dbSNP | Ensembl ].
    VAR_016795
    Natural varianti286 – 2861N → S in CLN2; enzymatically inactive; lacks one oligosaccharide chain resulting in enzymatic inactivation and possibly prelysosomal protein degradation; altered intracellular trafficking. 1 Publication
    Corresponds to variant rs119455958 [ dbSNP | Ensembl ].
    VAR_016796
    Natural varianti287 – 2871I → N in CLN2; displays no residual enzyme activity; altered intracellular trafficking. 1 Publication
    Corresponds to variant rs121908196 [ dbSNP | Ensembl ].
    VAR_009606
    Natural varianti339 – 3391R → Q in CLN2. 1 Publication
    VAR_066886
    Natural varianti343 – 3431E → K in CLN2; displays no residual enzyme activity; altered intracellular trafficking. 1 Publication
    Corresponds to variant rs121908197 [ dbSNP | Ensembl ].
    VAR_009607
    Natural varianti353 – 3531T → P in CLN2. 1 Publication
    Corresponds to variant rs121908206 [ dbSNP | Ensembl ].
    VAR_016797
    Natural varianti365 – 3651C → R in CLN2; displays no residual enzyme activity; altered intracellular trafficking. 2 Publications
    Corresponds to variant rs119455953 [ dbSNP | Ensembl ].
    VAR_005643
    Natural varianti365 – 3651C → Y in CLN2. 2 Publications
    Corresponds to variant rs119455954 [ dbSNP | Ensembl ].
    VAR_005644
    Natural varianti382 – 3821S → R in CLN2. 1 Publication
    VAR_066887
    Natural varianti385 – 3851V → D in CLN2. 1 Publication
    Corresponds to variant rs121908198 [ dbSNP | Ensembl ].
    VAR_009608
    Natural varianti389 – 3891G → E in CLN2. 1 Publication
    Corresponds to variant rs121908199 [ dbSNP | Ensembl ].
    VAR_009609
    Natural varianti422 – 4221Q → H in CLN2; displays no residual enzyme activity; altered intracellular trafficking. 1 Publication
    Corresponds to variant rs121908200 [ dbSNP | Ensembl ].
    VAR_009610
    Natural varianti428 – 4281K → N in CLN2. 1 Publication
    VAR_016798
    Natural varianti447 – 4471R → H in CLN2; displays very low residual enzyme activity; altered intracellular trafficking; demonstrates enhanced processing in response to folding improvement treatment; shows a five fold increase under permissive temperature conditions. 1 Publication
    Corresponds to variant rs119455956 [ dbSNP | Ensembl ].
    VAR_005645
    Natural varianti448 – 4481A → V in CLN2. 1 Publication
    VAR_066888
    Natural varianti454 – 4541A → E in CLN2. 1 Publication
    Corresponds to variant rs121908201 [ dbSNP | Ensembl ].
    VAR_009611
    Natural varianti466 – 4661V → G in SCAR7. 1 Publication
    VAR_070917
    Natural varianti473 – 4731G → R in CLN2. 2 Publications
    Corresponds to variant rs121908203 [ dbSNP | Ensembl ].
    VAR_016799
    Natural varianti475 – 4751S → L in CLN2; displays no residual enzyme activity; effectively transported to the lysosome. 1 Publication
    Corresponds to variant rs121908202 [ dbSNP | Ensembl ].
    VAR_009612
    Natural varianti481 – 4811F → C in CLN2. 1 Publication
    VAR_016800
    Natural varianti482 – 4821G → R in CLN2. 1 Publication
    Corresponds to variant rs121908208 [ dbSNP | Ensembl ].
    VAR_058435
    Natural varianti501 – 5011G → C in CLN2. 1 Publication
    VAR_066889
    Natural varianti504 – 5041N → Y in CLN2. 1 Publication
    VAR_066890
    Natural varianti544 – 5441P → S in CLN2; displays residual enzyme activity; effectively transported to the lysosome. 1 Publication
    Corresponds to variant rs121908210 [ dbSNP | Ensembl ].
    VAR_063641
    Natural varianti548 – 5481W → R in CLN2. 1 Publication
    VAR_066891

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 243243Missing in isoform 2. 1 PublicationVSP_013118Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF017456 mRNA. Translation: AAB80725.1.
    AF039704 Genomic DNA. Translation: AAC98480.1.
    AF491290 mRNA. Translation: AAM08412.1.
    AY268890 mRNA. Translation: AAQ72732.1.
    AY358502 mRNA. Translation: AAQ88866.1. Frameshift.
    AK222499 mRNA. Translation: BAD96219.1.
    BC014863 mRNA. Translation: AAH14863.1.
    CCDSiCCDS7770.1. [O14773-1]
    RefSeqiNP_000382.3. NM_000391.3. [O14773-1]
    UniGeneiHs.523454.

    Genome annotation databases

    EnsembliENST00000299427; ENSP00000299427; ENSG00000166340. [O14773-1]
    ENST00000533371; ENSP00000437066; ENSG00000166340. [O14773-2]
    GeneIDi1200.
    KEGGihsa:1200.
    UCSCiuc001mek.1. human. [O14773-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Cross-referencesi

    Web resourcesi

    NCL CLN2

    Neural Ceroid Lipofuscinoses mutation db

    Mendelian genes trieptidyl peptidase I (TPP1)

    Leiden Open Variation Database (LOVD)

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF017456 mRNA. Translation: AAB80725.1 .
    AF039704 Genomic DNA. Translation: AAC98480.1 .
    AF491290 mRNA. Translation: AAM08412.1 .
    AY268890 mRNA. Translation: AAQ72732.1 .
    AY358502 mRNA. Translation: AAQ88866.1 . Frameshift.
    AK222499 mRNA. Translation: BAD96219.1 .
    BC014863 mRNA. Translation: AAH14863.1 .
    CCDSi CCDS7770.1. [O14773-1 ]
    RefSeqi NP_000382.3. NM_000391.3. [O14773-1 ]
    UniGenei Hs.523454.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    1R60 model - A 196-563 [» ]
    3EDY X-ray 1.85 A 20-563 [» ]
    3EE6 X-ray 2.35 A/B 1-563 [» ]
    ProteinModelPortali O14773.
    SMRi O14773. Positions 20-563.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 107611. 8 interactions.
    DIPi DIP-47434N.
    IntActi O14773. 18 interactions.
    MINTi MINT-5002180.
    STRINGi 9606.ENSP00000299427.

    Protein family/group databases

    MEROPSi S53.003.

    PTM databases

    PhosphoSitei O14773.

    Proteomic databases

    MaxQBi O14773.
    PaxDbi O14773.
    PRIDEi O14773.

    Protocols and materials databases

    DNASUi 1200.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000299427 ; ENSP00000299427 ; ENSG00000166340 . [O14773-1 ]
    ENST00000533371 ; ENSP00000437066 ; ENSG00000166340 . [O14773-2 ]
    GeneIDi 1200.
    KEGGi hsa:1200.
    UCSCi uc001mek.1. human. [O14773-1 ]

    Organism-specific databases

    CTDi 1200.
    GeneCardsi GC11M006634.
    GeneReviewsi TPP1.
    H-InvDB HIX0009410.
    HGNCi HGNC:2073. TPP1.
    HPAi HPA037709.
    MIMi 204500. phenotype.
    607998. gene.
    609270. phenotype.
    neXtProti NX_O14773.
    Orphaneti 284324. Childhood-onset autosomal recessive slowly progressive spinocerebellar ataxia.
    228349. CLN2 disease.
    PharmGKBi PA26600.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG4934.
    HOGENOMi HOG000171253.
    HOVERGENi HBG004449.
    InParanoidi O14773.
    KOi K01279.
    OMAi CRVRSAR.
    OrthoDBi EOG7RNJZW.
    PhylomeDBi O14773.
    TreeFami TF333497.

    Enzyme and pathway databases

    BRENDAi 3.4.14.9. 2681.
    Reactomei REACT_18273. XBP1(S) activates chaperone genes.
    SABIO-RK O14773.
    SignaLinki O14773.

    Miscellaneous databases

    ChiTaRSi TPP1. human.
    EvolutionaryTracei O14773.
    GeneWikii Tripeptidyl_peptidase_I.
    GenomeRNAii 1200.
    NextBioi 4955.
    PMAP-CutDB O14773.
    PROi O14773.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi O14773.
    Bgeei O14773.
    CleanExi HS_TPP1.
    Genevestigatori O14773.

    Family and domain databases

    Gene3Di 3.40.50.200. 1 hit.
    InterProi IPR015366. Peptidase_S53_propep.
    IPR000209. Peptidase_S8/S53_dom.
    IPR009020. Prot_inh_propept.
    [Graphical view ]
    Pfami PF00082. Peptidase_S8. 1 hit.
    PF09286. Pro-kuma_activ. 1 hit.
    [Graphical view ]
    SMARTi SM00944. Pro-kuma_activ. 1 hit.
    [Graphical view ]
    SUPFAMi SSF52743. SSF52743. 1 hit.
    SSF54897. SSF54897. 1 hit.
    PROSITEi PS51695. SEDOLISIN. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis."
      Sleat D.E., Donnelly R.J., Lackland H., Liu C.-G., Sohar I., Pullarkat R.K., Lobel P.
      Science 277:1802-1805(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PARTIAL PROTEIN SEQUENCE, VARIANTS CLN2 ARG-365 AND TYR-365, VARIANT HIS-175.
      Tissue: Placenta.
    2. "Structural organization and sequence of CLN2, the defective gene in classical late infantile neuronal ceroid lipofuscinosis."
      Liu C.-G., Sleat D.E., Donnelly R.J., Lobel P.
      Genomics 50:206-212(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
      Tissue: Placenta.
    3. "Bovine brain homolog of the tripeptidyl peptidase I which is deficient in the human classic late-infantile neuronal ceroid lipofuscinosis."
      Junaid M.A., Barua M., Pullarkat R.K.
      Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
      Tissue: Brain cortex.
    4. "Identification of a human growth inhibition gene 1 (GIG1)."
      Kim J.W.
      Submitted (APR-2003) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
    5. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
    6. Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.
      Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
      Tissue: Adipose tissue.
    7. "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: Lymph.
    8. "The human CLN2 protein/tripeptidyl-peptidase I is a serine protease that autoactivates at acidic pH."
      Lin L., Sohar I., Lackland H., Lobel P.
      J. Biol. Chem. 276:2249-2255(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: PROTEIN SEQUENCE OF 20-24; 196-200 AND 466-492, MUTAGENESIS, CHARACTERIZATION.
    9. Cited for: SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS].
      Tissue: Melanoma.
    10. "Identification and quantification of N-linked glycoproteins using hydrazide chemistry, stable isotope labeling and mass spectrometry."
      Zhang H., Li X.-J., Martin D.B., Aebersold R.
      Nat. Biotechnol. 21:660-666(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: GLYCOSYLATION AT ASN-443.
    11. "Molecular basis of the neuronal ceroid lipofuscinoses: mutations in CLN1, CLN2, CLN3, and CLN5."
      Mole S.E., Mitchison H.M., Munroe P.B.
      Hum. Mutat. 14:199-215(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW ON VARIANTS.
    12. Cited for: SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS].
      Tissue: Melanoma.
    13. "Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry."
      Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.
      J. Proteome Res. 8:651-661(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-210; ASN-222; ASN-313 AND ASN-443.
      Tissue: Liver.
    14. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    15. "Structure of tripeptidyl-peptidase I provides insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis."
      Pal A., Kraetzner R., Gruene T., Grapp M., Schreiber K., Gronborg M., Urlaub H., Becker S., Asif A.R., Gartner J., Sheldrick G.M., Steinfeld R.
      J. Biol. Chem. 284:3976-3984(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.35 ANGSTROMS), ACTIVE SITE, CALCIUM-BINDING SITES, DISULFIDE BONDS, GLYCOSYLATION AT ASN-210; ASN-286; ASN-313 AND ASN-443.
    16. "Crystal structure and autoactivation pathway of the precursor form of human tripeptidyl-peptidase 1, the enzyme deficient in late infantile ceroid lipofuscinosis."
      Guhaniyogi J., Sohar I., Das K., Stock A.M., Lobel P.
      J. Biol. Chem. 284:3985-3997(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 20-563, ACTIVE SITE, DISULFIDE BONDS, CALCIUM-BINDING SITES, SUBUNIT, AUTOPROTEOLYTIC CLEAVAGE, GLYCOSYLATION AT ASN-210; ASN-286; ASN-313 AND ASN-443.
    17. "Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder."
      Sleat D.E., Gin R.M., Sohar I., Wisniewski K., Sklower-Brooks S., Pullarkat R.K., Palmer D.N., Lerner T.J., Boustany R.-M.N., Uldall P., Siakotos A.N., Donnelly R.J., Lobel P.
      Am. J. Hum. Genet. 64:1511-1523(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS CLN2 ARG-77; ASN-287; LYS-343; ARG-365; TYR-365; ASP-385; GLU-389; HIS-422; HIS-447; GLU-454 AND LEU-475, VARIANT ARG-100.
    18. "Prenatal testing for late infantile neuronal ceroid lipofuscinosis."
      Berry-Kravis E., Sleat D.E., Sohar I., Meyer P., Donnelly R., Lobel P.
      Ann. Neurol. 47:254-257(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT CLN2 CYS-206.
    19. "Heterogeneity of late-infantile neuronal ceroid lipofuscinosis."
      Zhong N., Moroziewicz D.N., Ju W., Jurkiewicz A., Johnston L., Wisniewski K.E., Brown W.T.
      Genet. Med. 2:312-318(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS CLN2 GLN-127; VAL-284; ASN-428 AND ARG-473.
    20. "Two novel CLN2 gene mutations in a Chinese patient with classical late-infantile neuronal ceroid lipofuscinosis."
      Lam C.W., Poon P.M., Tong S.F., Ko C.H.
      Am. J. Med. Genet. 99:161-163(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT CLN2 ARG-473.
    21. Cited for: VARIANT CLN2 LEU-202.
    22. "Expression and analysis of CLN2 variants in CHO cells: Q100R represents a polymorphism, and G389E and R447H represent loss-of-function mutations."
      Lin L., Lobel P.
      Hum. Mutat. 18:165-165(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: CHARACTERIZATION OF VARIANTS ARG-100; GLU-389 AND HIS-447.
    23. "Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical course in patients with CLN2 mutations."
      Steinfeld R., Heim P., von Gregory H., Meyer K., Ullrich K., Goebel H.H., Kohlschutter A.
      Am. J. Med. Genet. 112:347-354(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS CLN2 GLN-127; SER-286 AND PRO-353.
    24. "Identification of novel CLN2 mutations shows Canadian specific NCL2 alleles."
      Ju W., Zhong R., Moore S., Moroziewicz D., Currie J.R., Parfrey P., Brown W.T., Zhong N.
      J. Med. Genet. 39:822-825(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS CLN2 MET-277; PRO-278; VAL-284 AND CYS-481.
    25. "Tripeptidyl peptidase 1 deficiency in neuronal ceroid lipofuscinosis. A novel mutation."
      Bukina A.M., Tsvetkova I.V., Semiachkina A.N., Il'ina E.S.
      Vopr. Med. Khim. 48:594-598(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT CLN2 HIS-206.
    26. "Mutation of the glycosylated asparagine residue 286 in human CLN2 protein results in loss of enzymatic activity."
      Tsiakas K., Steinfeld R., Storch S., Ezaki J., Lukacs Z., Kominami E., Kohlschuetter A., Ullrich K., Braulke T.
      Glycobiology 14:1C-5C(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: CHARACTERIZATION OF VARIANT CLN2 SER-286.
    27. "Mutations in CLN7/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis."
      Kousi M., Siintola E., Dvorakova L., Vlaskova H., Turnbull J., Topcu M., Yuksel D., Gokben S., Minassian B.A., Elleder M., Mole S.E., Lehesjoki A.-E.
      Brain 132:810-819(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT CLN2 ARG-482.
    28. "Functional consequences and rescue potential of pathogenic missense mutations in tripeptidyl peptidase I."
      Walus M., Kida E., Golabek A.A.
      Hum. Mutat. 31:710-721(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT CLN2 SER-544, CHARACTERIZATION OF VARIANTS CLN2 ARG-77; GLN-127; LEU-202; CYS-206; MET-277; VAL-284; SER-286; ASN-287; LYS-343; ARG-365; HIS-422; HIS-447; LEU-475 AND SER-544.
    29. "Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses."
      Kousi M., Lehesjoki A.E., Mole S.E.
      Hum. Mutat. 33:42-63(2012) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS CLN2 THR-62; HIS-209; GLN-266; GLN-339; ARG-382; VAL-448; CYS-501; TYR-504 AND ARG-548.
    30. "Autosomal recessive spinocerebellar ataxia 7 (SCAR7) is caused by variants in TPP1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (CLN2 disease)."
      Sun Y., Almomani R., Breedveld G.J., Santen G.W., Aten E., Lefeber D.J., Hoff J.I., Brusse E., Verheijen F.W., Verdijk R.M., Kriek M., Oostra B., Breuning M.H., Losekoot M., den Dunnen J.T., van de Warrenburg B.P., Maat-Kievit A.J.
      Hum. Mutat. 34:706-713(2013) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT SCAR7 GLY-466.

    Entry informationi

    Entry nameiTPP1_HUMAN
    AccessioniPrimary (citable) accession number: O14773
    Secondary accession number(s): Q53HT1
    , Q5JAK6, Q6UX56, Q71JP6, Q96C37
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: December 15, 1998
    Last sequence update: May 30, 2006
    Last modified: October 1, 2014
    This is version 156 of the entry and version 2 of the sequence. [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, Direct protein sequencing, Reference proteome

    Documents

    1. Human chromosome 11
      Human chromosome 11: 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

    External Data

    Dasty 3