Tripeptidyl peptidase I

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TPP1
3EE6.png
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTPP1, CLN2, LPIC, SCAR7, TPP-1, GIG1, Tripeptidyl peptidase I, tripeptidyl peptidase 1
External IDsMGI: 1336194 HomoloGene: 335 GeneCards: TPP1
Gene location (Human)
Chromosome 11 (human)
Chr.Chromosome 11 (human)[1]
Chromosome 11 (human)
Genomic location for TPP1
Genomic location for TPP1
Band11p15.4Start6,612,763 bp[1]
End6,619,485 bp[1]
RNA expression pattern
PBB GE TPP1 200742 s at fs.png

PBB GE TPP1 200743 s at fs.png

PBB GE TPP1 214196 s at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000391

NM_009906

RefSeq (protein)

NP_000382

NP_034036

Location (UCSC)Chr 11: 6.61 – 6.62 MbChr 7: 105.74 – 105.75 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Tripeptidyl-peptidase 1, also known as Lysosomal pepstatin-insensitive protease, is an enzyme that in humans is encoded by the TPP1 gene.[5][6] TPP1 should not be confused with the TPP1 shelterin protein which protects telomeres and is encoded by the ACD gene.[7] Mutations in the TPP1 gene leads to late infantile neuronal ceroid lipofuscinosis.[8]

Structure[edit]

Gene[edit]

The human gene TPP1 encodes a member of the sedolisin family of serine proteases. The human gene has 13 exons and locates at the chromosome band 11p15.[6]

Protein[edit]

The human TPP1 is 61kDa in size and composed of 563 amino acids. An isoform of 34.5kDa and 320 amino acids is generated by alternative splicing and a peptide fragment of 1-243 amino acid is missing.[9] TPP1 contains a globular structure with a subtilisin-like fold, a Ser475-Glu272-Asp360 catalytic triad. It also contains an octahedrally coordinated Ca2+-binding site that are characteristic features of the S53 sedolisin family of peptidases. Unlike other S53 peptidases, it has steric constraints on the P4 substrate pocket, which might contribute to its preferential cleavage of tripeptides from the unsubstituted N-terminus of proteins. Two alternative conformations of the catalytic Asp276 are associated with the activation status of TPP1.[10]

Function[edit]

High expression of TPP1 is found in bone marrow, placenta, lung, pineal and lymphocytes. The protease functions in the lysosome to cleave N-terminal tripeptides from substrates and has weaker endopeptidase activity. It is synthesized as a catalytically inactive enzyme which is activated and autoproteolyzed upon acidification.

Clinical significance[edit]

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders with pathological phenotypes that auto fluorescent lipopigments present in neurons and other cell types. Over the past two decades, accumulating evidences indicates that NCLs are caused by mutations in eight different genes, including genes encoding several soluble proteins (cathepsin D, PPT1, and TPP1).[11] Mutations of gene TPP1 result in late-infantile neuronal ceroid lipofuscinosis which is associated with the failure to degrade specific neuropeptides and a subunit of ATP synthase in the lysosome.[12] Mutations in the TPP1 gene lead to late infantile neuronal ceroid lipofuscinosis, a fatal neurodegenerative disease of childhood.[10] It has been demonstrated that a single injection of intravitreal implantation of autologous bone marrow derived stem cells transduced with a TPP1 expression construct at an early stage in the disease progression could substantially inhibit the development of disease-related retinal function deficits and structural changes. This result implies that ex vivo gene therapy using autologous stem cells may be an effective means of achieving sustained delivery of therapeutic compounds to tissues such as the retina for which systemic administration would be ineffective.[13]

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000166340 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030894 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:".
  4. ^ "Mouse PubMed Reference:".
  5. ^ Liu CG, Sleat DE, Donnelly RJ, Lobel P (June 1998). "Structural organization and sequence of CLN2, the defective gene in classical late infantile neuronal ceroid lipofuscinosis". Genomics. 50 (2): 206–12. doi:10.1006/geno.1998.5328. PMID 9653647.
  6. ^ a b "Entrez Gene: TPP1 tripeptidyl peptidase I".
  7. ^ "ACD ACD, shelterin complex subunit and telomerase recruitment factor [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-02-03.
  8. ^ Bukina AM, Tsvetkova IV, Semiachkina AN, Il'ina ES (Nov 2002). "[Tripeptidyl peptidase 1 deficiency in neuronal ceroid lipofuscinosis. A novel mutation]". Voprosy Medit︠s︡inskoĭ Khimii. 48 (6): 594–8. PMID 12698559.
  9. ^ "Uniprot: O14773 - TPP1_HUMAN".
  10. ^ a b Pal A, Kraetzner R, Gruene T, Grapp M, Schreiber K, Grønborg M, Urlaub H, Becker S, Asif AR, Gärtner J, Sheldrick GM, Steinfeld R (February 2009). "Structure of tripeptidyl-peptidase I provides insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis". The Journal of Biological Chemistry. 284 (6): 3976–84. doi:10.1074/jbc.M806947200. PMID 19038966.
  11. ^ Getty AL, Pearce DA (February 2011). "Interactions of the proteins of neuronal ceroid lipofuscinosis: clues to function". Cellular and Molecular Life Sciences. 68 (3): 453–74. doi:10.1007/s00018-010-0468-6. PMC 4120758. PMID 20680390.
  12. ^ Gardiner RM (2000). "The molecular genetic basis of the neuronal ceroid lipofuscinoses". Neurological Sciences. 21 (3 Suppl): S15–9. PMID 11073223.
  13. ^ Tracy CJ, Whiting RE, Pearce JW, Williamson BG, Vansteenkiste DP, Gillespie LE, Castaner LJ, Bryan JN, Coates JR, Jensen CA, Katz ML (September 2016). "Intravitreal implantation of TPP1-transduced stem cells delays retinal degeneration in canine CLN2 neuronal ceroid lipofuscinosis". Experimental Eye Research. 152: 77–87. doi:10.1016/j.exer.2016.09.003. PMID 27637672.

Further reading[edit]

External links[edit]