Tripeptidyl peptidase I

TPP1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3EDY, 3EE6
Identifiers
Aliases	TPP1, CLN2, LPIC, SCAR7, TPP-1, GIG1, Tripeptidyl peptidase I, tripeptidyl peptidase 1
External IDs	MGI: 1336194 HomoloGene: 335 GeneCards: TPP1
Gene ontology Molecular function • tripeptidyl-peptidase activity • peptide binding • endopeptidase activity • metal ion binding • peptidase activity • protein binding • serine-type peptidase activity • serine-type endopeptidase activity • hydrolase activity Cellular component • melanosome • lysosomal lumen • mitochondrion • lysosome • extracellular exosome Biological process • epithelial cell differentiation • neuromuscular process controlling balance • lipid metabolic process • bone resorption • nervous system development • proteolysis • central nervous system development • IRE1-mediated unfolded protein response • protein catabolic process • lysosome organization • peptide catabolic process Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1200	12751
Ensembl	ENSG00000166340	ENSMUSG00000030894
UniProt	O14773	O89023
RefSeq (mRNA)	NM_000391	NM_009906
RefSeq (protein)	NP_000382.3	NP_034036.1
Location (UCSC)	Chr 11: 6.61 – 6.62 Mb	Chr 7: 105.74 – 105.75 Mb
PubMed search	[1]	[2]
Wikidata

Tripeptidyl-peptidase 1, also known as Lysosomal pepstatin-insensitive protease, is an enzyme that in humans is encoded by the TPP1 gene.^[3][4] TPP1 mainly functions as a regulator of telomerase recruitment, activation, and regulation.^[5] Mutations in the TPP1 gene leads to late infantile neuronal ceroid lipofuscinosis.^[6]

Structure

Gene

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.^[4]

Protein

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.^[7] 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.^[8]

Function

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. TPP1 is a component of the telomere-specific shelterin complex, which facilitats the replication of the double-stranded telomeric DNA tracts and protects the telomeric end from unregulated DNA repair activities. TPP1 mainly functions as a regulator of telomerase recruitment, activation, and regulation.^[5] Although TPP1 was originally described as a bridging factor between TRF1 and TRF2, which participate in a pathway with POT1 as a negative regulator of telomerase-dependent telomere length control, ^[9] more recent studies suggest that TPP1 could directly promotes telomerase activity at the telomere.^[10] A part of the TPP1 oligonucleotide/oligosaccharide-binding (OB) fold named TEL patch that interacts with the catalytic subunit of telomerase, hTERT, has been proven essential for telomerase activation.^[11] What’s more, TPP1 has been demonstrated the only pathway required for recruitment of telomerase to chromosome ends, and it also defines telomere length homeostasis in hESCs.^[11]

Clinical significance

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).^[12] 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.^[13] Mutations in the TPP1 gene lead to late infantile neuronal ceroid lipofuscinosis, a fatal neurodegenerative disease of childhood.^[8] 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 inhibite 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.^[14]

Interaction

• POT1 ^[15]
• hTERT ^{[10] [9]}
• TIN2 ^[16]
• TRF1 ^[16]
• TRF2 ^[16]
• Telomerase ^[17]

References

Further reading

External links

• The MEROPS online database for peptidases and their inhibitors: S53.003
• GeneReviews/NCBI/NIH/UW entry on Neuronal Ceroid-Lipofuscinoses