Tripeptidyl peptidase II explained

Tripeptidyl-peptidase 2 is an enzyme that in humans is encoded by the TPP2 gene.^{[1] [2]} Among other things it is heavily implicated in MHC (HLA) class-I processing, as it has both endopeptidase and exopeptidase activity.^[3]

Clinical significance and genetic deficiency

Biallelic deleterious variants in the TPP2 gene may result in a recessive disorder with immune deficiency, autoimmune disease and intellectual disability.^{[4] [5]} Some genetic variants may result in a milder disease with sterile brain inflammation mimicking multiple sclerosis.^[6] These observations underline the fundamental role of TPP2 in cells of the immune system.

External links

• The MEROPS online database for peptidases and their inhibitors: S08.090

Further reading

• Tomkinson B, Zetterqvist O . Immunological cross-reactivity between human tripeptidyl peptidase II and fibronectin . The Biochemical Journal . 267 . 1 . 149–154 . April 1990 . 1691635 . 1131257 . 10.1042/bj2670149 .
• Tomkinson B . Nucleotide sequence of cDNA covering the N-terminus of human tripeptidyl peptidase II . Biomedica Biochimica Acta . 50 . 4–6 . 727–729 . 1992 . 1840501 .
• Tomkinson B, Wernstedt C, Hellman U, Zetterqvist O . Active site of tripeptidyl peptidase II from human erythrocytes is of the subtilisin type . Proceedings of the National Academy of Sciences of the United States of America . 84 . 21 . 7508–7512 . November 1987 . 3313395 . 299325 . 10.1073/pnas.84.21.7508 . 1987PNAS...84.7508T . free .
• Wilson C, Gibson AM, McDermott JR . Purification and characterization of tripeptidylpeptidase-II from post-mortem human brain . Neurochemical Research . 18 . 7 . 743–749 . July 1993 . 8396212 . 10.1007/BF00966768 . 21957759 .
• Martinsson T, Vujic M, Tomkinson B . Localization of the human tripeptidyl peptidase II gene (TPP2) to 13q32-q33 by nonradioactive in situ hybridization and somatic cell hybrids . Genomics . 17 . 2 . 493–495 . August 1993 . 8406500 . 10.1006/geno.1993.1353 .
• Rose C, Vargas F, Facchinetti P, Bourgeat P, Bambal RB, Bishop PB, Chan SM, Moore AN, Ganellin CR, Schwartz JC . 6 . Characterization and inhibition of a cholecystokinin-inactivating serine peptidase . Nature . 380 . 6573 . 403–409 . April 1996 . 8602240 . 10.1038/380403a0 . 1996Natur.380..403R . vanc . 4269327 .
• Geier E, Pfeifer G, Wilm M, Lucchiari-Hartz M, Baumeister W, Eichmann K, Niedermann G . A giant protease with potential to substitute for some functions of the proteasome . Science . 283 . 5404 . 978–981 . February 1999 . 9974389 . 10.1126/science.283.5404.978 . vanc .
• Ganellin CR, Bishop PB, Bambal RB, Chan SM, Law JK, Marabout B, Luthra PM, Moore AN, Peschard O, Bourgeat P, Rose C, Vargas F, Schwartz JC . 6 . Inhibitors of tripeptidyl peptidase II. 2. Generation of the first novel lead inhibitor of cholecystokinin-8-inactivating peptidase: a strategy for the design of peptidase inhibitors . Journal of Medicinal Chemistry . 43 . 4 . 664–674 . February 2000 . 10691692 . 10.1021/jm990226g . vanc .
• Lévy F, Burri L, Morel S, Peitrequin AL, Lévy N, Bachi A, Hellman U, Van den Eynde BJ, Servis C . 6 . The final N-terminal trimming of a subaminoterminal proline-containing HLA class I-restricted antigenic peptide in the cytosol is mediated by two peptidases . Journal of Immunology . 169 . 8 . 4161–4171 . October 2002 . 12370345 . 10.4049/jimmunol.169.8.4161 . vanc . free .
• Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA . 6 . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proceedings of the National Academy of Sciences of the United States of America . 99 . 26 . 16899–16903 . December 2002 . 12477932 . 139241 . 10.1073/pnas.242603899 . 2002PNAS...9916899M . vanc . free .
• Lindås AC, Tomkinson B . Identification and characterization of the promoter for the gene encoding human tripeptidyl-peptidase II . Gene . 345 . 2 . 249–257 . January 2005 . 15716107 . 10.1016/j.gene.2004.11.042 .
• Stavropoulou V, Vasquez V, Cereser B, Freda E, Masucci MG . TPPII promotes genetic instability by allowing the escape from apoptosis of cells with activated mitotic checkpoints . Biochemical and Biophysical Research Communications . 346 . 2 . 415–425 . July 2006 . 16762321 . 10.1016/j.bbrc.2006.05.141 . vanc .
• York IA, Bhutani N, Zendzian S, Goldberg AL, Rock KL . Tripeptidyl peptidase II is the major peptidase needed to trim long antigenic precursors, but is not required for most MHC class I antigen presentation . Journal of Immunology . 177 . 3 . 1434–1443 . August 2006 . 16849449 . 10.4049/jimmunol.177.3.1434 . vanc . free .
• Lindås AC, Tomkinson B . Characterization of the promoter of the gene encoding human tripeptidyl-peptidase II and identification of upstream silencer elements . Gene . 393 . 1–2 . 62–69 . May 2007 . 17343995 . 10.1016/j.gene.2007.01.015 .

Notes and References

1. Tomkinson B, Jonsson AK . Characterization of cDNA for human tripeptidyl peptidase II: the N-terminal part of the enzyme is similar to subtilisin . Biochemistry . 30 . 1 . 168–174 . January 1991 . 1670990 . 10.1021/bi00215a025 .
2. Web site: Entrez Gene: TPP2 tripeptidyl peptidase II.
3. Reits E, Neijssen J, Herberts C, Benckhuijsen W, Janssen L, Drijfhout JW, Neefjes J . A major role for TPPII in trimming proteasomal degradation products for MHC class I antigen presentation . Immunity . 20 . 4 . 495–506 . April 2004 . 15084277 . 10.1016/S1074-7613(04)00074-3 . vanc . free .
4. Lu W, Zhang Y, McDonald DO, Jing H, Carroll B, Robertson N, Zhang Q, Griffin H, Sanderson S, Lakey JH, Morgan NV, Reynard LN, Zheng L, Murdock HM, Turvey SE, Hackett SJ, Prestidge T, Hall JM, Cant AJ, Matthews HF, Koref MF, Simon AK, Korolchuk VI, Lenardo MJ, Hambleton S, Su HC . 6 . Dual proteolytic pathways govern glycolysis and immune competence . Cell . 159 . 7 . 1578–1590 . December 2014 . 25525876 . 10.1016/j.cell.2014.12.001. 4297473 .
5. Atallah I, Quinodoz M, Campos-Xavier B, Peter VG, Fouriki A, Bonvin C, Bottani A, Kumps C, Angelini F, Bellutti Enders F, Christen-Zaech S, Rizzi M, Renella R, Beck-Popovic M, Poloni C, Frossard V, Blouin JL, Rivolta C, Riccio O, Candotti F, Hofer M, Unger S, Superti-Furga A . 6 . Immune deficiency, autoimmune disease and intellectual disability: A pleiotropic disorder caused by biallelic variants in the TPP2 gene . Clinical Genetics . 99 . 6 . 780–788 . June 2021 . 33586135 . 10.1111/cge.13942 . 231926886 .
6. Reinthaler EM, Graf E, Zrzavy T, Wieland T, Hotzy C, Kopecky C, Pferschy S, Schmied C, Leutmezer F, Keilani M, Lill CM, Hoffjan S, Epplen JT, Zettl UK, Hecker M, Deutschländer A, Meuth SG, Ahram M, Mustafa B, El-Khateeb M, Vilariño-Güell C, Sadovnick AD, Zimprich F, Tomkinson B, Strom T, Kristoferitsch W, Lassmann H, Zimprich A . 6 . TPP2 mutation associated with sterile brain inflammation mimicking MS . Neurology. Genetics . 4 . 6 . e285 . December 2018 . 30533531 . 10.1212/NXG.0000000000000285 . 6244017 .