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Reviewed, UniProtKB/Swiss-Prot O14773 (TPP1_HUMAN)

Last modified June 16, 2009. Version 99. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Alternative products · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended name:
    Tripeptidyl-peptidase 1
      Short name=TPP-1
    EC=3.4.14.9
Alternative name(s):
    Tripeptidyl-peptidase I
      Short name=TPP-I
    Tripeptidyl aminopeptidase
    Lysosomal pepstatin-insensitive protease
      Short name=LPIC
    Cell growth-inhibiting gene 1 protein
Gene names
Name: TPP1
Synonyms: CLN2
ORF Names: GIG1, UNQ267/PRO304
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length563 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level.

General annotation (Comments)

Function

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.

Catalytic activity

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

Subcellular location

Lysosome. Melanosome. Note: Identified by mass spectrometry in melanosome fractions from stage I to stage IV. Ref.9 Ref.12

Tissue specificity

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

Post-translational modification

Activated by autocatalytic proteolytical processing upon acidification.

Involvement in disease

Defects in TPP1 are the cause of classical late-infantile neuronal ceroid lipofuscinosis (LINCL) [MIM:204500]; also known as ceroid lipofuscinosis neuronal 2 (CLN2). LINCL is a fatal childhood neurodegenerative disease characterized by progressive visual and mental decline, motor disturbance, epilepsy and behavioral changes. The three main subtypes of childhood NCLs defined by the age of onset, clinical features, and ultrastructural morphology are infantile NCL (INCL), classical late-infantile NCL (LINCL), or juvenile NCL (JNCL), although a number of other distinct variants forms have been described. Ref.1 Ref.15 Ref.16 Ref.17 Ref.18 Ref.20 Ref.21 Ref.22

Sequence similarities

Belongs to the peptidase S53 family.

Caution

Ref.3 sequence is wrongly reported to originate from bovine.

Sequence caution

The sequence AAQ88866.1 differs from that shown. Reason: Frameshift at position 551.

Ontologies

Keywords
   Cellular componentLysosome
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDisease mutation
Epilepsy
Neuronal ceroid lipofuscinosis
   DomainSignal
   Molecular functionHydrolase
Protease
Serine protease
   PTMGlycoprotein
Zymogen
   Technical term3D-structure
Direct protein sequencing
Gene Ontology (GO)
   Biological processbone resorption

Inferred from mutant phenotype. Source: UniProtKB

lipid metabolic process Ref.1

Traceable author statement. Source: ProtInc

lysosome organization

Inferred from sequence or structural similarity. Source: UniProtKB

nervous system development Ref.1

Inferred from mutant phenotype. Source: UniProtKB

neuromuscular process controlling balance

Inferred from sequence or structural similarity. Source: UniProtKB

peptide catabolic process

Inferred from mutant phenotype. Source: UniProtKB

proteolysis Ref.1

Inferred from mutant phenotype. Source: UniProtKB

   Cellular componentlysosome Ref.1

Inferred from direct assay. Source: UniProtKB

melanosome

Inferred from electronic annotation. Source: UniProtKB-SubCell

mitochondrion

Inferred from sequence or structural similarity. Source: UniProtKB

soluble fraction

Inferred from direct assay. Source: UniProtKB

   Molecular functionpeptide binding

Inferred from sequence or structural similarity. Source: UniProtKB

protein binding

Inferred from physical interaction. Source: UniProtKB

serine-type endopeptidase activity

Inferred from electronic annotation. Source: InterPro

tripeptidyl-peptidase activity Ref.8

Inferred from direct assay. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: O14773-1)

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: O14773-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-243: Missing.
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 1919 Ref.8
Propeptide20 – 195176Removed in mature form
PRO_0000027374
Chain196 – 563368Tripeptidyl-peptidase 1
PRO_0000027375

Sites

Active site2721Charge relay system By similarity
Active site2761Charge relay system By similarity
Active site4751Charge relay system By similarity

Amino acid modifications

Glycosylation2101N-linked (GlcNAc...)
Glycosylation2221N-linked (GlcNAc...)
Glycosylation2861N-linked (GlcNAc...) Potential
Glycosylation3131N-linked (GlcNAc...)
Glycosylation4431N-linked (GlcNAc...) Ref.10

Natural variations

Alternative sequence1 – 243243Missing in isoform 2.
VSP_013118
Natural variant621S → L: dbSNP rs2734715.
VAR_037572
Natural variant771G → R in LINCL. Ref.15
VAR_009603
Natural variant1001Q → R: dbSNP rs1800746. Ref.15 Ref.19
VAR_009604
Natural variant1271R → Q in LINCL. Ref.17 Ref.20
VAR_016790
Natural variant1531S → P in LINCL.
VAR_016791
Natural variant1751R → H Ref.1
VAR_005642
Natural variant1851R → C: dbSNP rs34758634.
VAR_037573
Natural variant2061R → C in LINCL. dbSNP rs28940573. Ref.16 Ref.22
VAR_009605
Natural variant2061R → H in LINCL. Ref.16 Ref.22
VAR_016792
Natural variant2771V → M in LINCL. Ref.21
VAR_016793
Natural variant2781Q → P in LINCL. Ref.21
VAR_016794
Natural variant2841G → V in LINCL. Ref.17 Ref.21
VAR_016795
Natural variant2861N → S in LINCL. Ref.20
VAR_016796
Natural variant2871I → N in LINCL. Ref.15
VAR_009606
Natural variant3431E → K in LINCL. Ref.15
VAR_009607
Natural variant3531T → P in LINCL. Ref.20
VAR_016797
Natural variant3651C → R in LINCL. Ref.1 Ref.15
VAR_005643
Natural variant3651C → Y in LINCL. Ref.1 Ref.15
VAR_005644
Natural variant3851V → D in LINCL. Ref.15
VAR_009608
Natural variant3891G → E in LINCL. Ref.15
VAR_009609
Natural variant4221Q → H in LINCL. Ref.15
VAR_009610
Natural variant4281K → N in LINCL. Ref.17
VAR_016798
Natural variant4471R → H in LINCL. Ref.15
VAR_005645
Natural variant4541A → E in LINCL. Ref.15
VAR_009611
Natural variant4731G → R in LINCL. Ref.17 Ref.18
VAR_016799
Natural variant4751S → L in LINCL. Ref.15
VAR_009612
Natural variant4811F → C in LINCL. Ref.21
VAR_016800

Experimental info

Mutagenesis2361H → A: No effect.
Mutagenesis3601D → A: Inactive. Impaired processing.
Mutagenesis4751S → A: Inactive. Impaired processing.
Mutagenesis5171D → A: Inactive. Impaired processing.
Sequence conflict1151I → N in BAD96219. Ref.6
Sequence conflict3731Q → E in AAH14863. Ref.7

Secondary structure

................................................................ 563
Helix Strand Turn

Details...

Sequences

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

Last modified May 30, 2006. Version 2.
Checksum: 7299D902F6AE8555

FASTA56361,248
        10         20         30         40         50         60 
MGLQACLLGL FALILSGKCS YSPEPDQRRT LPPGWVSLGR ADPEEELSLT FALRQQNVER 

        70         80         90        100        110        120 
LSELVQAVSD PSSPQYGKYL TLENVADLVR PSPLTLHTVQ KWLLAAGAQK CHSVITQDFL 

       130        140        150        160        170        180 
TCWLSIRQAE LLLPGAEFHH YVGGPTETHV VRSPHPYQLP QALAPHVDFV GGLHRFPPTS 

       190        200        210        220        230        240 
SLRQRPEPQV TGTVGLHLGV TPSVIRKRYN LTSQDVGSGT SNNSQACAQF LEQYFHDSDL 

       250        260        270        280        290        300 
AQFMRLFGGN FAHQASVARV VGQQGRGRAG IEASLDVQYL MSAGANISTW VYSSPGRHEG 

       310        320        330        340        350        360 
QEPFLQWLML LSNESALPHV HTVSYGDDED SLSSAYIQRV NTELMKAAAR GLTLLFASGD 

       370        380        390        400        410        420 
SGAGCWSVSG RHQFRPTFPA SSPYVTTVGG TSFQEPFLIT NEIVDYISGG GFSNVFPRPS 

       430        440        450        460        470        480 
YQEEAVTKFL SSSPHLPPSS YFNASGRAYP DVAALSDGYW VVSNRVPIPW VSGTSASTPV 

       490        500        510        520        530        540 
FGGILSLINE HRILSGRPPL GFLNPRLYQQ HGAGLFDVTR GCHESCLDEE VEGQGFCSGP 

       550        560 
GWDPVTGWGT PNFPALLKTL LNP 

« Hide

Isoform 2.

Checksum: 707AE6D4A90B0FBC
Show »

FASTA32034,464

References

« Hide 'large scale' references
[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: 9295267] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PARTIAL PROTEIN SEQUENCE, VARIANTS LINCL 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: 9653647] [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]"The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment."
Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E. expand/collapse author list , Heldens S., Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.
Genome Res. 13:2265-2270(2003) [PubMed: 12975309] [Abstract]
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: 15489334] [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: 11054422] [Abstract]
Cited for: PROTEIN SEQUENCE OF 20-24; 196-200 AND 466-492, MUTAGENESIS, CHARACTERIZATION.
[9]"Proteomic analysis of early melanosomes: identification of novel melanosomal proteins."
Basrur V., Yang F., Kushimoto T., Higashimoto Y., Yasumoto K., Valencia J., Muller J., Vieira W.D., Watabe H., Shabanowitz J., Hearing V.J., Hunt D.F., Appella E.
J. Proteome Res. 2:69-79(2003) [PubMed: 12643545] [Abstract]
Cited for: SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[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: 12754519] [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: 10477428] [Abstract]
Cited for: REVIEW ON VARIANTS.
[12]"Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes."
Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H., Mangini N.J., Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R., Yamagishi S., Shabanowitz J., Hearing V.J., Wu C., Appella E., Hunt D.F.
J. Proteome Res. 5:3135-3144(2006) [PubMed: 17081065] [Abstract]
Cited for: SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[13]Colinge J., Superti-Furga G., Bennett K.L.
Submitted (OCT-2008) to UniProtKB
Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[14]"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: 19159218] [Abstract]
Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-210; ASN-222; ASN-313 AND ASN-443, MASS SPECTROMETRY.
Tissue: Liver.
[15]"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: 10330339] [Abstract]
Cited for: VARIANTS LINCL 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.
[16]"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: 10665500] [Abstract]
Cited for: VARIANT LINCL CYS-206.
[17]"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: 11339651] [Abstract]
Cited for: VARIANTS LINCL GLN-127; VAL-284; ASN-428 AND ARG-473.
[18]"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: 11241479] [Abstract]
Cited for: VARIANT LINCL ARG-473.
[19]"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: 11462245] [Abstract]
Cited for: CHARACTERIZATION OF VARIANTS ARG-100; GLU-389 AND HIS-447.
[20]"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: 12376936] [Abstract]
Cited for: VARIANTS LINCL GLN-127; SER-286 AND PRO-353.
[21]"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: 12414822] [Abstract]
Cited for: VARIANTS LINCL MET-277; PRO-278; VAL-284 AND CYS-481.
[22]"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: 12698559] [Abstract]
Cited for: VARIANT LINCL HIS-206.
+Additional computationally mapped references.

Web resources

NCL CLN2

Neural Ceroid Lipofuscinoses mutation db

GeneReviews

Cross-references

Sequence databases

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.
IPIIPI00298237.
IPI00554617.
RefSeqNP_000382.3.
UniGeneHs.523454

3D structure databases

EntryMethodResolution (Å)ChainPositionsPDBsum
1R60model-A196-563[»]
3EDYX-ray1.85A20-563[»]
3EE6X-ray2.35A/B1-563[»]
ModBaseSearch...

Protein family/group databases

MEROPSS53.003.

PTM databases

PhosphoSiteO14773.

Proteomic databases

PRIDEO14773.

Genome annotation databases

EnsemblENSG00000166340. Homo sapiens. [Contig view]
GeneID1200.
KEGGhsa:1200.

Organism-specific databases

GeneCardsGC11M006591.
H-InvDBHIX0009410.
HGNCHGNC:2073. TPP1.
MIM204500. phenotype.
607998. gene.
Orphanet216. Ceroid lipofuscinosis, neuronal.
168491. Late infantile neuronal ceroid lipofuscinosis.
PharmGKBPA26600.
GenAtlasSearch...

Phylogenomic databases

HOGENOMO14773.
HOVERGENO14773.
OMAO14773. SVIRKRY.

Enzyme and pathway databases

BRENDA3.4.14.9. 247.

Gene expression databases

ArrayExpressO14773.
BgeeO14773.
CleanExHS_TPP1.
GermOnlineENSG00000166340. Homo sapiens.

Family and domain databases

InterProIPR000209. Pept_S8_S53.
IPR015366. Peptidase_S53_propep.
[Graphical view]
Gene3DG3DSA:3.40.50.200. Pept_S8_S53. 1 hit.
PfamPF09286. Pro-kuma_activ. 1 hit.
[Graphical view]
ProtoNetSearch...

Other Resources

NextBio4955.
PMAP-CutDBO14773.
SOURCESearch...

Entry information

Entry nameTPP1_HUMAN
AccessionPrimary (citable) accession number: O14773
Secondary accession number(s): Q53HT1 expand/collapse secondary AC list , Q5JAK6, Q6UX56, Q71JP6, Q96C37
Entry history
Integrated into UniProtKB/Swiss-Prot: December 15, 1998
Last sequence update: May 30, 2006
Last modified: June 16, 2009
This is version 99 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation projectHPI (Human Proteome Initiative)

Relevant documents

Human chromosome 11

Human chromosome 11: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

Peptidase families

Classification of peptidase families and list of entries

SIMILARITY comments

Index of protein domains and families

Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Alternative products · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents