Biology:DPP9
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Dipeptidyl peptidase 9 is an enzyme that in humans is encoded by the DPP9 gene.[1]
This gene encodes a protein that is a member of the S9B family in clan SC of the serine proteases. The protein has been shown to have post-proline dipeptidyl aminopeptidase activity, cleaving Xaa-Pro dipeptides from the N-termini of proteins. Although the activity of this protein is similar to that of dipeptidyl peptidase 4 (DPP4), it does not appear to be membrane bound.
In general, dipeptidyl peptidases appear to be involved in the regulation of the activity of their substrates and have been linked to a variety of diseases including type 2 diabetes, obesity and cancer. Several transcript variants of this gene have been described but not fully characterized.[1] More specifically, DPP9 interacts with the NLRP1 protein and affects the level of activation of the NLPR1 inflammasome. This function involves binding to a complex of full length NLRP1 and a proinflammatory fragment of NLRP1 after activation by autocleavage.[2][3] A similiar mechanism allows DPP9 to regulate the CARD8 inflammasome. [4]
This gene has also been linked to severe COVID-19.
Medical Genetics
Mutations in NLRP1 that block DPP9 interaction lead to a rare Mendelian condition called Autoinflammation with Arthritis and Dyskeratosis[5][6] A homozygous recessive syndrome dubbed Hatipoğlu syndrome is attributed to mutations in DPP9 with phenotype of failure to thrive, skin manifestations, pancytopenia, and susceptibility to infections.[7] Genetic analysis of knockout alleles of DPP9 in mice and zebrafish showed a severe phenotype that could be rescued by mutation of NLPR1 in the same report.
References
- ↑ 1.0 1.1 "Entrez Gene: DPP9 dipeptidyl-peptidase 9". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=91039.
- ↑ "DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation". Nature 592 (7856): 778–783. April 2021. doi:10.1038/s41586-021-03350-4. PMID 33731932.
- ↑ "Structural and biochemical mechanisms of NLRP1 inhibition by DPP9". Nature 592 (7856): 773–777. April 2021. doi:10.1038/s41586-021-03320-w. PMID 33731929.
- ↑ "Dipeptidyl peptidase 9 sets a threshold for CARD8 inflammasome formation by sequestering its active C-terminal fragment". Immunity 54 (7): 1392–1404.e10. July 2021. doi:10.1016/j.immuni.2021.04.024. PMID 34019797.
- ↑ "Autoinflammation With Arthritis and Dyskeratosis; AIADK". https://www.omim.org/entry/617388.
- ↑ "Human DPP9 represses NLRP1 inflammasome and protects against autoinflammatory diseases via both peptidase activity and FIIND domain binding". The Journal of Biological Chemistry 293 (49): 18864–18878. December 2018. doi:10.1074/jbc.RA118.004350. PMID 30291141.
- ↑ Harapas, Cassandra R.; Robinson, Kim S.; Lay, Kenneth; Wong, Jasmine; Moreno Traspas, Ricardo; Nabavizadeh, Nasrin; Rass-Rothschild, Annick; Boisson, Bertrand et al. (September 2022). "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling". Science Immunology 7 (75): eabi4611. doi:10.1126/sciimmunol.abi4611. PMID 36112693.
Further reading
- "Identification and characterization of human DPP9, a novel homologue of dipeptidyl peptidase IV". Gene 299 (1–2): 185–193. October 2002. doi:10.1016/S0378-1119(02)01059-4. PMID 12459266.
- "Structural requirements for catalysis, expression, and dimerization in the CD26/DPIV gene family". Biochemistry 42 (3): 694–701. January 2003. doi:10.1021/bi026846s. PMID 12534281.
- "Cloning and characterization of dipeptidyl peptidase 10, a new member of an emerging subgroup of serine proteases". The Biochemical Journal 373 (Pt 1): 179–189. July 2003. doi:10.1042/BJ20021914. PMID 12662155.
- "Dipeptidyl peptidase 9 has two forms, a broad tissue distribution, cytoplasmic localization and DPIV-like peptidase activity". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression 1679 (1): 18–28. July 2004. doi:10.1016/j.bbaexp.2004.03.010. PMID 15245913.
- "Isoforms of dipeptidyl aminopeptidase IV from Pseudomonas sp. WO24: role of the signal sequence and overexpression in Escherichia coli". Protein Expression and Purification 41 (2): 241–251. June 2005. doi:10.1016/j.pep.2004.10.027. PMID 15866709.
- "Dipeptidyl peptidases 8 and 9: specificity and molecular characterization compared with dipeptidyl peptidase IV". The Biochemical Journal 396 (2): 391–399. June 2006. doi:10.1042/BJ20060079. PMID 16475979.
- DP8 and DP9 have extra-enzymatic roles in cell adhesion, migration and apoptosis. Advances in Experimental Medicine and Biology. 575. 2006. pp. 63–72. doi:10.1007/0-387-32824-6_7. ISBN 978-0-387-29058-4. PMID 16700509.
- "Extraenzymatic functions of the dipeptidyl peptidase IV-related proteins DP8 and DP9 in cell adhesion, migration and apoptosis". The FEBS Journal 273 (11): 2447–2460. June 2006. doi:10.1111/j.1742-4658.2006.05253.x. PMID 16704418.
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