Tripeptidyl peptidase I

(Redirected from TPP1)

Tripeptidyl-peptidase 1, also known as Lysosomal pepstatin-insensitive protease, is an enzyme that in humans is encoded by the TPP1 gene, also known as CLN2.[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]

TPP1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTPP1, CLN2, LPIC, SCAR7, TPP-1, GIG1, Tripeptidyl peptidase I, tripeptidyl peptidase 1
External IDsOMIM: 607998; MGI: 1336194; HomoloGene: 335; GeneCards: TPP1; OMA:TPP1 - orthologs
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: 105.39 – 105.4 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

edit

Gene

edit

The human gene TPP1 encodes a member of the sedolisin family of serine protease enzymes. The human gene has 13 exons and locates at the chromosome band 11p15.[6] It is also known as CLN2, due to the relation to the disease.

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.[10] 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. Bi-allelic mutations of the gene TPP1 have been found to result in one of these disorders, called late-infantile neuronal ceroid lipofuscinosis, also known as CLN type 2 or Jansky–Bielschowsky disease.[11] Mutations of gene is associated with the failure to degrade specific neuropeptides and a subunit of ATP synthase in the lysosome and accumulation of the fluorescent pigments.[12] The disease causes childhood onset neurodegeneration resulting in epilepsy, movement disorders and progressive loss of motor and cognitive skills.[13][14] Additionally, it causes retinal degeneration resulting in progressive loss of vision. Enzyme replacement therapy with cerliponase alfa can alter this course of disease, and is licensed for use in several countries.[15]

References

edit
  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000166340Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030894Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  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 Meditsinskoi 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. hdl:11858/00-001M-0000-0012-D8E3-A. PMID 19038966.
  11. ^ Williams, Ruth E.; Mole, Sara E. (2012-07-10). "New nomenclature and classification scheme for the neuronal ceroid lipofuscinoses". Neurology. 79 (2): 183–191. doi:10.1212/WNL.0b013e31825f0547. ISSN 0028-3878. PMID 22778232.
  12. ^ Gardiner RM (2000). "The molecular genetic basis of the neuronal ceroid lipofuscinoses". Neurological Sciences. 21 (3 Suppl): S15–9. doi:10.1007/s100720070035. PMID 11073223. S2CID 9550598.
  13. ^ Worgall, S.; Kekatpure, M. V.; Heier, L.; Ballon, D.; Dyke, J. P.; Shungu, D.; Mao, X.; Kosofsky, B.; Kaplitt, M. G.; Souweidane, M. M.; Sondhi, D.; Hackett, N. R.; Hollmann, C.; Crystal, R. G. (2007-08-07). "Neurological deterioration in late infantile neuronal ceroid lipofuscinosis". Neurology. 69 (6): 521–535. doi:10.1212/01.wnl.0000267885.47092.40. ISSN 0028-3878. PMID 17679671.
  14. ^ Spaull, Robert; Soo, Audrey K.; Batzios, Spyros; Footitt, Emma; Whiteley, Rebecca; Mink, Jonathan W.; Carr, Lucinda; Gissen, Paul; Kurian, Manju A. (2024-08-13). "Evolution of Movement Disorders in Patients With CLN2-Batten Disease Treated With Enzyme Replacement Therapy". Neurology. 103 (3): e209615. doi:10.1212/WNL.0000000000209615. ISSN 0028-3878. PMC 11314953. PMID 38976822.
  15. ^ Schulz, Angela; Ajayi, Temitayo; Specchio, Nicola; de Los Reyes, Emily; Gissen, Paul; Ballon, Douglas; Dyke, Jonathan P.; Cahan, Heather; Slasor, Peter; Jacoby, David; Kohlschütter, Alfried (2018-05-17). "Study of Intraventricular Cerliponase Alfa for CLN2 Disease". New England Journal of Medicine. 378 (20): 1898–1907. doi:10.1056/NEJMoa1712649. ISSN 0028-4793. PMID 29688815.

Further reading

edit
edit