DPP9_MOUSE
ID DPP9_MOUSE Reviewed; 862 AA.
AC Q8BVG4; Q6KAM9; Q8BWT9;
DT 07-JUN-2005, integrated into UniProtKB/Swiss-Prot.
DT 07-JUN-2005, sequence version 2.
DT 03-AUG-2022, entry version 138.
DE RecName: Full=Dipeptidyl peptidase 9 {ECO:0000303|PubMed:24223149};
DE Short=DP9;
DE EC=3.4.14.5 {ECO:0000269|PubMed:24223149};
DE AltName: Full=Dipeptidyl peptidase IX;
DE Short=DPP IX;
DE AltName: Full=Dipeptidyl peptidase-like protein 9;
DE Short=DPLP9;
GN Name=Dpp9 {ECO:0000303|PubMed:24223149, ECO:0000312|MGI:MGI:2443967};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=C57BL/6J; TISSUE=Liver, and Olfactory bulb;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Thymus;
RX PubMed=15449545; DOI=10.1093/dnares/11.2.127;
RA Okazaki N., Kikuno R., Ohara R., Inamoto S., Koseki H., Hiraoka S.,
RA Saga Y., Kitamura H., Nakagawa T., Nagase T., Ohara O., Koga H.;
RT "Prediction of the coding sequences of mouse homologues of FLJ genes: the
RT complete nucleotide sequences of 110 mouse FLJ-homologous cDNAs identified
RT by screening of terminal sequences of cDNA clones randomly sampled from
RT size-fractionated libraries.";
RL DNA Res. 11:127-135(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=FVB/N; TISSUE=Salivary gland;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Heart, Liver, Lung, Pancreas, and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF SER-729, ACTIVE SITE,
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=24223149; DOI=10.1371/journal.pone.0078378;
RA Gall M.G., Chen Y., Vieira de Ribeiro A.J., Zhang H., Bailey C.G.,
RA Spielman D.S., Yu D.M., Gorrell M.D.;
RT "Targeted inactivation of dipeptidyl peptidase 9 enzymatic activity causes
RT mouse neonate lethality.";
RL PLoS ONE 8:E78378-E78378(2013).
RN [6]
RP MUTAGENESIS OF SER-729, ACTIVE SITE, TISSUE SPECIFICITY, AND DEVELOPMENTAL
RP STAGE.
RX PubMed=28887018; DOI=10.1016/j.ydbio.2017.09.001;
RA Kim M., Minoux M., Piaia A., Kueng B., Gapp B., Weber D., Haller C.,
RA Barbieri S., Namoto K., Lorenz T., Wirsching J., Bassilana F., Dietrich W.,
RA Rijli F.M., Ksiazek I.;
RT "DPP9 enzyme activity controls survival of mouse migratory tongue muscle
RT progenitors and its absence leads to neonatal lethality due to suckling
RT defect.";
RL Dev. Biol. 431:297-308(2017).
RN [7]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=27820798; DOI=10.1038/nchembio.2229;
RA Okondo M.C., Johnson D.C., Sridharan R., Go E.B., Chui A.J., Wang M.S.,
RA Poplawski S.E., Wu W., Liu Y., Lai J.H., Sanford D.G., Arciprete M.O.,
RA Golub T.R., Bachovchin W.W., Bachovchin D.A.;
RT "DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and
RT macrophage pyroptosis.";
RL Nat. Chem. Biol. 13:46-53(2017).
RN [8]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=29396289; DOI=10.1016/j.chembiol.2017.12.013;
RA Okondo M.C., Rao S.D., Taabazuing C.Y., Chui A.J., Poplawski S.E.,
RA Johnson D.C., Bachovchin D.A.;
RT "Inhibition of Dpp8/9 activates the Nlrp1b inflammasome.";
RL Cell Chem. Biol. 25:262-267(2018).
CC -!- FUNCTION: Dipeptidyl peptidase that cleaves off N-terminal dipeptides
CC from proteins having a Pro or Ala residue at position 2
CC (PubMed:24223149). Acts as a key inhibitor of caspase-1-dependent
CC monocyte and macrophage pyroptosis in resting cells by preventing
CC activation of NLRP1 and CARD8 (PubMed:27820798, PubMed:29396289).
CC Sequesters the cleaved C-terminal part of NLRP1 and CARD8, which
CC respectively constitute the active part of the NLRP1 and CARD8
CC inflammasomes, in a ternary complex, thereby preventing their
CC oligomerization and activation (By similarity). The dipeptidyl
CC peptidase activity is required to suppress NLRP1 and CARD8; however,
CC neither NLRP1 nor CARD8 are bona fide substrates of DPP9, suggesting
CC the existence of substrate(s) required for NLRP1 and CARD8 inhibition
CC (By similarity). {ECO:0000250|UniProtKB:Q86TI2,
CC ECO:0000269|PubMed:24223149, ECO:0000269|PubMed:27820798,
CC ECO:0000269|PubMed:29396289}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Release of an N-terminal dipeptide, Xaa-Yaa-|-Zaa-, from a
CC polypeptide, preferentially when Yaa is Pro, provided Zaa is neither
CC Pro nor hydroxyproline.; EC=3.4.14.5;
CC Evidence={ECO:0000269|PubMed:24223149};
CC -!- ACTIVITY REGULATION: Inhibited by the serine proteinase inhibitor 4-(2-
CC aminoethyl)benzenesulphonyl fluoride (AEBSF), and by di-
CC isopropylfluorophosphate (By similarity). Inhibited by Val-boroPro
CC (Talabostat, PT-100), a non-selective inhibitor, which triggers
CC pyroptosis in monocytes and macrophages (PubMed:27820798,
CC PubMed:29396289). Val-boroPro inhibits activity by binding to the
CC active site, mimicking a substrate-bound state, thereby displacing the
CC C-terminal fragment of NLRP1, leading to activation of the NLRP1
CC inflammasome. In contrast, Val-boroPro does not directly displaces
CC CARD8: it acts by promoting degradation of the N-terminal part of
CC CARD8, leading to indirect disruption of the ternary complex (By
CC similarity). {ECO:0000250|UniProtKB:Q86TI2,
CC ECO:0000269|PubMed:27820798, ECO:0000269|PubMed:29396289}.
CC -!- SUBUNIT: Homodimer. Forms a ternary complex with NLRP1, composed of a
CC DPP9 homodimer, one full-length NLRP1 protein, and one cleaved C-
CC terminus of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, C-
CC terminus). Forms a ternary complex with CARD8, composed of a DPP9
CC homodimer, one full-length NLRP1 protein, and one cleaved C-terminus of
CC CARD8 (Caspase recruitment domain-containing protein 8, C-terminus). In
CC the ternary complex, only one subunit of the DPP9 homodimer is bound to
CC NLRP1 or CARD8. {ECO:0000250|UniProtKB:Q86TI2}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:24223149}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8BVG4-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8BVG4-2; Sequence=VSP_013870, VSP_013871, VSP_013872;
CC -!- TISSUE SPECIFICITY: Detected in kidney, skin, brain, thymus and liver
CC (at protein level). {ECO:0000269|PubMed:24223149,
CC ECO:0000269|PubMed:28887018}.
CC -!- DEVELOPMENTAL STAGE: Detected in hypoglossal cord and first branchial
CC arch at 10.75 dpc (at protein level). {ECO:0000269|PubMed:28887018}.
CC -!- SIMILARITY: Belongs to the peptidase S9B family. DPPIV subfamily.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAD21428.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AK050021; BAC34034.1; -; mRNA.
DR EMBL; AK078301; BAC37211.1; -; mRNA.
DR EMBL; AK131178; BAD21428.1; ALT_SEQ; mRNA.
DR EMBL; BC057631; AAH57631.1; -; mRNA.
DR CCDS; CCDS37663.1; -. [Q8BVG4-1]
DR RefSeq; NP_766212.2; NM_172624.3. [Q8BVG4-1]
DR RefSeq; XP_006524218.1; XM_006524155.3. [Q8BVG4-1]
DR AlphaFoldDB; Q8BVG4; -.
DR SMR; Q8BVG4; -.
DR BioGRID; 230336; 7.
DR STRING; 10090.ENSMUSP00000046604; -.
DR ChEMBL; CHEMBL3259484; -.
DR ESTHER; mouse-dpp9; DPP4N_Peptidase_S9.
DR MEROPS; S09.019; -.
DR iPTMnet; Q8BVG4; -.
DR PhosphoSitePlus; Q8BVG4; -.
DR EPD; Q8BVG4; -.
DR jPOST; Q8BVG4; -.
DR MaxQB; Q8BVG4; -.
DR PaxDb; Q8BVG4; -.
DR PeptideAtlas; Q8BVG4; -.
DR PRIDE; Q8BVG4; -.
DR ProteomicsDB; 277602; -. [Q8BVG4-1]
DR ProteomicsDB; 277603; -. [Q8BVG4-2]
DR Antibodypedia; 23705; 410 antibodies from 29 providers.
DR DNASU; 224897; -.
DR Ensembl; ENSMUST00000038794; ENSMUSP00000046604; ENSMUSG00000001229. [Q8BVG4-1]
DR GeneID; 224897; -.
DR KEGG; mmu:224897; -.
DR UCSC; uc008dbh.2; mouse. [Q8BVG4-1]
DR CTD; 91039; -.
DR MGI; MGI:2443967; Dpp9.
DR VEuPathDB; HostDB:ENSMUSG00000001229; -.
DR eggNOG; KOG2281; Eukaryota.
DR GeneTree; ENSGT00940000158174; -.
DR HOGENOM; CLU_006105_1_0_1; -.
DR InParanoid; Q8BVG4; -.
DR OMA; VTHMTPQ; -.
DR OrthoDB; 137965at2759; -.
DR PhylomeDB; Q8BVG4; -.
DR TreeFam; TF313309; -.
DR BioGRID-ORCS; 224897; 7 hits in 72 CRISPR screens.
DR ChiTaRS; Dpp9; mouse.
DR PRO; PR:Q8BVG4; -.
DR Proteomes; UP000000589; Chromosome 17.
DR RNAct; Q8BVG4; protein.
DR Bgee; ENSMUSG00000001229; Expressed in dorsal pancreas and 225 other tissues.
DR Genevisible; Q8BVG4; MM.
DR GO; GO:0031252; C:cell leading edge; ISO:MGI.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005874; C:microtubule; ISO:MGI.
DR GO; GO:0004177; F:aminopeptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0008239; F:dipeptidyl-peptidase activity; ISS:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0008236; F:serine-type peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR GO; GO:0070269; P:pyroptosis; ISS:UniProtKB.
DR Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR029058; AB_hydrolase.
DR InterPro; IPR045785; Dpp_8/9_N.
DR InterPro; IPR001375; Peptidase_S9.
DR InterPro; IPR002469; Peptidase_S9B_N.
DR Pfam; PF19520; Dpp_8_9_N; 1.
DR Pfam; PF00930; DPPIV_N; 1.
DR Pfam; PF00326; Peptidase_S9; 1.
DR SUPFAM; SSF53474; SSF53474; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Aminopeptidase; Cytoplasm; Hydrolase; Protease;
KW Reference proteome; Serine protease.
FT CHAIN 1..862
FT /note="Dipeptidyl peptidase 9"
FT /id="PRO_0000122416"
FT ACT_SITE 729
FT /note="Charge relay system"
FT /evidence="ECO:0000269|PubMed:28887018,
FT ECO:0000305|PubMed:24223149"
FT ACT_SITE 807
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:Q6V1X1"
FT ACT_SITE 839
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:Q6V1X1"
FT BINDING 729
FT /ligand="Val-boroPro"
FT /ligand_id="ChEBI:CHEBI:187904"
FT /ligand_note="inhibitor"
FT /note="covalent"
FT /evidence="ECO:0000250|UniProtKB:Q86TI2"
FT VAR_SEQ 1..75
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15449545"
FT /id="VSP_013870"
FT VAR_SEQ 748..787
FT /note="VAIAGAPVTVWMAYDTGYTERYMDVPENNQQGYEAGSVAL -> PPHEAESP
FT SSLPATTDPRMASASSSMWEAKPGTPASEGQR (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15449545"
FT /id="VSP_013871"
FT VAR_SEQ 788..862
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15449545"
FT /id="VSP_013872"
FT MUTAGEN 729
FT /note="S->A: Decreased levels of global dipeptidyl
FT peptidase activity. Homozygous pups are born at the
FT expected Mendelian rate and display no obvious
FT morphological defects, but none survive to weaning.
FT Homozygous pups display suckling defects and survive only
FT when fed manually. The suckling defects are probably due to
FT increased apoptosis of migratory tongue muscle progenitor
FT cells, leading to defects in the development of intrinsic
FT muscles in the distal tongue and decreased tongue size."
FT /evidence="ECO:0000269|PubMed:24223149,
FT ECO:0000269|PubMed:28887018"
FT CONFLICT 369
FT /note="D -> Y (in Ref. 1; BAC37211)"
FT /evidence="ECO:0000305"
FT CONFLICT 546
FT /note="S -> F (in Ref. 2; BAD21428)"
FT /evidence="ECO:0000305"
FT CONFLICT 777
FT /note="Q -> K (in Ref. 1; BAC37211)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 862 AA; 98001 MW; B1D566E824A834E8 CRC64;
MCSGVSPVEQ VAAGDMDDTA ARFCVQKHSW DGLRSIIHGS RKSSGLIVSK APHDFQFVQK
PDESGPHSHR LYYLGMPYGS RENSLLYSEI PKKVRKEALL LLSWKQMLDH FQATPHHGVY
SREEELLRER KRLGVFGITS YDFHSESGLF LFQASNSLFH CRDGGKNGFM VSPMKPLEIK
TQCSGPRMDP KICPADPAFF SFINNSDLWV ANIETGEERR LTFCHQGSAG VLDNPKSAGV
ATFVIQEEFD RFTGCWWCPT ASWEGSEGLK TLRILYEEVD ESEVEVIHVP SPALEERKTD
SYRYPRTGSK NPKIALKLAE LQTDHQGKIV SSCEKELVQP FSSLFPKVEY IARAGWTRDG
KYAWAMFLDR PQQRLQLVLL PPALFIPAVE SEAQRQAAAR AVPKNVQPFV IYEEVTNVWI
NVHDIFHPFP QAEGQQDFCF LRANECKTGF CHLYRVTVEL KTKDYDWTEP LSPTEDEFKC
PIKEEVALTS GEWEVLSRHG SKIWVNEQTK LVYFQGTKDT PLEHHLYVVS YESAGEIVRL
TTLGFSHSCS MSQSFDMFVS HYSSVSTPPC VHVYKLSGPD DDPLHKQPRF WASMMEAANC
PPDYVPPEIF HFHTRADVQL YGMIYKPHTL QPGRKHPTVL FVYGGPQVQL VNNSFKGIKY
LRLNTLASLG YAVVVIDGRG SCQRGLHFEG ALKNQMGQVE IEDQVEGLQY VAEKYGFIDL
SRVAIHGWSY GGFLSLMGLI HKPQVFKVAI AGAPVTVWMA YDTGYTERYM DVPENNQQGY
EAGSVALHVE KLPNEPNRLL ILHGFLDENV HFFHTNFLVS QLIRAGKPYQ LQIYPNERHS
IRCRESGEHY EVTLLHFLQE HL
