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O14773

- TPP1_HUMAN

UniProt

O14773 - TPP1_HUMAN

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Protein

Tripeptidyl-peptidase 1

Gene

TPP1

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

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. serine-type endopeptidase activity Source: InterPro
  6. serine-type peptidase activity Source: UniProtKB
  7. 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
Complete GO annotation...

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: UniProtKB
  2. lysosomal lumen Source: Reactome
  3. lysosome Source: UniProtKB
  4. mitochondrion Source: Ensembl
Complete GO annotation...

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

BgeeiO14773.
CleanExiHS_TPP1.
ExpressionAtlasiO14773. baseline and differential.
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 – 406Combined sources
Beta strandi46 – 538Combined sources
Helixi58 – 6912Combined sources
Turni74 – 774Combined sources
Helixi82 – 898Combined sources
Helixi93 – 10614Combined sources
Beta strandi109 – 1135Combined sources
Beta strandi119 – 1257Combined sources
Helixi126 – 1327Combined sources
Beta strandi139 – 1435Combined sources
Turni144 – 1474Combined sources
Beta strandi148 – 1525Combined sources
Helixi161 – 1633Combined sources
Turni164 – 1663Combined sources
Beta strandi167 – 1704Combined sources
Helixi202 – 2087Combined sources
Beta strandi219 – 2213Combined sources
Beta strandi224 – 2296Combined sources
Helixi237 – 24711Combined sources
Beta strandi258 – 2625Combined sources
Helixi271 – 28313Combined sources
Turni284 – 2863Combined sources
Beta strandi287 – 2926Combined sources
Turni295 – 3006Combined sources
Helixi303 – 3119Combined sources
Beta strandi319 – 3246Combined sources
Helixi329 – 3313Combined sources
Helixi334 – 34916Combined sources
Beta strandi353 – 3575Combined sources
Beta strandi366 – 3683Combined sources
Beta strandi371 – 3733Combined sources
Turni379 – 3813Combined sources
Beta strandi385 – 39713Combined sources
Beta strandi402 – 4043Combined sources
Beta strandi411 – 4177Combined sources
Helixi420 – 4223Combined sources
Helixi423 – 43210Combined sources
Helixi439 – 4413Combined sources
Beta strandi446 – 4494Combined sources
Beta strandi451 – 4555Combined sources
Beta strandi457 – 4637Combined sources
Beta strandi466 – 4716Combined sources
Helixi474 – 49421Combined sources
Helixi504 – 5096Combined sources
Turni510 – 5145Combined sources
Beta strandi522 – 5254Combined sources
Turni529 – 5335Combined sources
Beta strandi534 – 5374Combined sources
Turni544 – 5463Combined sources
Helixi553 – 5586Combined sources

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.
GeneTreeiENSGT00390000008684.
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

        10         20         30         40         50
MGLQACLLGL FALILSGKCS YSPEPDQRRT LPPGWVSLGR ADPEEELSLT
60 70 80 90 100
FALRQQNVER LSELVQAVSD PSSPQYGKYL TLENVADLVR PSPLTLHTVQ
110 120 130 140 150
KWLLAAGAQK CHSVITQDFL TCWLSIRQAE LLLPGAEFHH YVGGPTETHV
160 170 180 190 200
VRSPHPYQLP QALAPHVDFV GGLHRFPPTS SLRQRPEPQV TGTVGLHLGV
210 220 230 240 250
TPSVIRKRYN LTSQDVGSGT SNNSQACAQF LEQYFHDSDL AQFMRLFGGN
260 270 280 290 300
FAHQASVARV VGQQGRGRAG IEASLDVQYL MSAGANISTW VYSSPGRHEG
310 320 330 340 350
QEPFLQWLML LSNESALPHV HTVSYGDDED SLSSAYIQRV NTELMKAAAR
360 370 380 390 400
GLTLLFASGD SGAGCWSVSG RHQFRPTFPA SSPYVTTVGG TSFQEPFLIT
410 420 430 440 450
NEIVDYISGG GFSNVFPRPS YQEEAVTKFL SSSPHLPPSS YFNASGRAYP
460 470 480 490 500
DVAALSDGYW VVSNRVPIPW VSGTSASTPV FGGILSLINE HRILSGRPPL
510 520 530 540 550
GFLNPRLYQQ HGAGLFDVTR GCHESCLDEE VEGQGFCSGP GWDPVTGWGT
560
PNFPALLKTL LNP
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]
ENST00000611494; ENSP00000484546; ENSG00000166340.
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 ]
ENST00000611494 ; ENSP00000484546 ; ENSG00000166340 .
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.
GeneTreei ENSGT00390000008684.
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

Bgeei O14773.
CleanExi HS_TPP1.
ExpressionAtlasi O14773. baseline and differential.
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

« Hide 'large scale' publications
  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 29, 2014
This is version 157 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