Q86TI2 · DPP9_HUMAN
- ProteinDipeptidyl peptidase 9
- GeneDPP9
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids863 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Acts as a key inhibitor of caspase-1-dependent monocyte and macrophage pyroptosis in resting cells by preventing activation of NLRP1 and CARD8 (PubMed:27820798, PubMed:29967349, PubMed:30291141, PubMed:31525884, PubMed:32796818, PubMed:36112693, PubMed:36357533).
Sequesters the cleaved C-terminal part of NLRP1 and CARD8, which respectively constitute the active part of the NLRP1 and CARD8 inflammasomes, in a ternary complex, thereby preventing their oligomerization and activation (PubMed:33731929, PubMed:33731932, PubMed:34019797).
The dipeptidyl peptidase activity is required to suppress NLRP1 and CARD8; however, neither NLRP1 nor CARD8 are bona fide substrates of DPP9, suggesting the existence of substrate(s) required for NLRP1 and CARD8 inhibition (PubMed:33731929).
Catalytic activity
Activity regulation
Inhibited by Val-boroPro (Talabostat, PT-100), a non-selective inhibitor, which triggers pyroptosis in monocytes and macrophages (PubMed:27820798, PubMed:29967349, PubMed:32796818, PubMed:33731932, PubMed:36357533).
Val-boroPro inhibits activity by binding to the active site, mimicking a substrate-bound state, thereby displacing the C-terminal fragment of NLRP1, leading to activation of the NLRP1 inflammasome (PubMed:33731932, PubMed:34019797, PubMed:36357533).
In contrast, Val-boroPro does not directly displaces CARD8: it acts by promoting degradation of the N-terminal part of CARD8, leading to indirect disruption of the ternary complex (PubMed:34019797).
Chemical inhibition of DPP9 by Val-boroPro in HIV-1-infected cells activates the CARD8 inflammasome, triggering cell death, offering a promising strategy for the elimination of HIV-1 reservoirs in people living with HIV-1 (PubMed:36357533).
Kinetics
KM | SUBSTRATE | pH | TEMPERATURE[C] | NOTES | EVIDENCE | |
---|---|---|---|---|---|---|
161 μM | Ala-Pro-AMC | |||||
180 μM | Ala-Pro-AFC | |||||
222 μM | Gly-Pro-AMC | |||||
122 μM | Lys-Pro-AMC | |||||
72.6 μM | Trp-Pro-AMC | |||||
96 μM | Val-Pro-AMC |
kcat is 52.6 sec-1 with Lys-Pro-AMC substrate (PubMed:29382749).
kcat is 54 sec-1 with Asp-Pro-AMC substrate (PubMed:29382749).
kcat is 40.3 sec-1 with Trp-Pro-AMC substrate (PubMed:29382749).
kcat is 79.9 sec-1 with Val-Pro-AMC substrate (PubMed:29382749).
pH Dependence
Features
Showing features for active site, binding site.
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | cell leading edge | |
Cellular Component | cytosol | |
Cellular Component | microtubule | |
Cellular Component | nucleus | |
Molecular Function | aminopeptidase activity | |
Molecular Function | dipeptidyl-peptidase activity | |
Molecular Function | identical protein binding | |
Molecular Function | serine-type peptidase activity | |
Biological Process | negative regulation of programmed cell death | |
Biological Process | proteolysis | |
Biological Process | pyroptotic inflammatory response |
Keywords
- Molecular function
Enzyme and pathway databases
Protein family/group databases
DPP9 limits the presentation of the RU1 antigen on MHC class I alleles.
Ligand binding to DPP9 induces an extensive rearrangement at the active site through a disorder-order transition of a 26-residue loop segment, which partially folds into an alpha-helix (R-helix), including Arg-133, a key residue for substrate binding.
DPP9 is a dipeptidyl peptidase that cleaves after prolines.
DPP9 binds in a non-covalent manner to the E67 interacting loop (EIL) of SUMO1. Identification of the SUMO-binding arm in DPP9 (SUBA domain). SUMO1 acts as an allosteric regulator of DPP9.
DPP9 regulates B-cell receptor mediated signaling by processing SYK N-terminus. DPP9 plays a role in the N-degron pathway.
Names & Taxonomy
Protein names
- Recommended nameDipeptidyl peptidase 9
- EC number
- Short namesDP9
- Alternative names
Gene names
- Community suggested namesDPP9
- Community suggested namesDPP9-L; DPP9-S.
- Community suggested namesDPP9
- Community suggested namesDPP9
- Community suggested namesDPP9
- Community suggested namesDPP9
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionQ86TI2
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Isoform 1
Isoform 2
Keywords
- Cellular component
Disease & Variants
Involvement in disease
Hatipoglu immunodeficiency syndrome (HATIS)
- Note
- DescriptionAn autosomal recessive immunologic disorder manifesting in infancy or early childhood, and characterized by failure to thrive, short stature, skin pigmentation abnormalities, pancytopenia, and susceptibility to recurrent infections.
- See alsoMIM:620331
Natural variants in HATIS
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_088502 | 82-863 | missing | in HATIS; likely pathogenic | |
VAR_088503 | 138 | G>S | in HATIS; likely pathogenic; decreased dipeptidyl-peptidase activity; less able to maintain NLRP1 in the inactive state | |
VAR_088504 | 185-863 | missing | in HATIS; likely pathogenic | |
VAR_088505 | 822-863 | missing | in HATIS; likely pathogenic; no protein detected by Wester blot analysis in homozygous patient cells |
Features
Showing features for natural variant, mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_088502 | 82-863 | in HATIS; likely pathogenic | |||
Sequence: Missing | ||||||
Mutagenesis | 96-97 | Reduced interaction with CARD8 without affecting the peptidase activity. | ||||
Sequence: RK → EE | ||||||
Mutagenesis | 100-101 | Reduced interaction with NLRP1 and CARD8 without affecting the peptidase activity. | ||||
Sequence: LL → EE | ||||||
Mutagenesis | 102 | Reduced interaction with NLRP1 without affecting the peptidase activity. | ||||
Sequence: L → E | ||||||
Mutagenesis | 102-103 | Reduced interaction with CARD8 without affecting the peptidase activity. | ||||
Sequence: LL → EE | ||||||
Natural variant | VAR_088503 | 138 | in HATIS; likely pathogenic; decreased dipeptidyl-peptidase activity; less able to maintain NLRP1 in the inactive state | |||
Sequence: G → S | ||||||
Natural variant | VAR_088504 | 185-863 | in HATIS; likely pathogenic | |||
Sequence: Missing | ||||||
Mutagenesis | 597 | Reduced interaction with NLRP1 without affecting the peptidase activity. | ||||
Sequence: E → R | ||||||
Mutagenesis | 730 | Abolished dipeptidyl peptidase activity and ability to sequester NLRP1 and inhibit pyroptosis. | ||||
Sequence: S → A | ||||||
Natural variant | VAR_088505 | 822-863 | in HATIS; likely pathogenic; no protein detected by Wester blot analysis in homozygous patient cells | |||
Sequence: Missing |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 974 variants from UniProt as well as other sources including ClinVar and dbSNP.
Keywords
- Disease
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for initiator methionine, modified residue, chain, modified residue (large scale data).
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Initiator methionine | 1 | UniProt | Removed | ||||
Sequence: M | |||||||
Modified residue | 2 | UniProt | N-acetylalanine | ||||
Sequence: A | |||||||
Chain | PRO_0000122415 | 2-863 | UniProt | Dipeptidyl peptidase 9 | |||
Sequence: ATTGTPTADRGDAAATDDPAARFQVQKHSWDGLRSIIHGSRKYSGLIVNKAPHDFQFVQKTDESGPHSHRLYYLGMPYGSRENSLLYSEIPKKVRKEALLLLSWKQMLDHFQATPHHGVYSREEELLRERKRLGVFGITSYDFHSESGLFLFQASNSLFHCRDGGKNGFMVSPMKPLEIKTQCSGPRMDPKICPADPAFFSFINNSDLWVANIETGEERRLTFCHQGLSNVLDDPKSAGVATFVIQEEFDRFTGYWWCPTASWEGSEGLKTLRILYEEVDESEVEVIHVPSPALEERKTDSYRYPRTGSKNPKIALKLAEFQTDSQGKIVSTQEKELVQPFSSLFPKVEYIARAGWTRDGKYAWAMFLDRPQQWLQLVLLPPALFIPSTENEEQRLASARAVPRNVQPYVVYEEVTNVWINVHDIFYPFPQSEGEDELCFLRANECKTGFCHLYKVTAVLKSQGYDWSEPFSPGEDEFKCPIKEEIALTSGEWEVLARHGSKIWVNEETKLVYFQGTKDTPLEHHLYVVSYEAAGEIVRLTTPGFSHSCSMSQNFDMFVSHYSSVSTPPCVHVYKLSGPDDDPLHKQPRFWASMMEAASCPPDYVPPEIFHFHTRSDVRLYGMIYKPHALQPGKKHPTVLFVYGGPQVQLVNNSFKGIKYLRLNTLASLGYAVVVIDGRGSCQRGLRFEGALKNQMGQVEIEDQVEGLQFVAEKYGFIDLSRVAIHGWSYGGFLSLMGLIHKPQVFKVAIAGAPVTVWMAYDTGYTERYMDVPENNQHGYEAGSVALHVEKLPNEPNRLLILHGFLDENVHFFHTNFLVSQLIRAGKPYQLQIYPNERHSIRCPESGEHYEVTLLHFLQEYL | |||||||
Modified residue (large scale data) | 4 | PRIDE | Phosphothreonine | ||||
Sequence: T | |||||||
Modified residue (large scale data) | 6 | PRIDE | Phosphothreonine | ||||
Sequence: T | |||||||
Modified residue (large scale data) | 173 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 835 | PRIDE | Phosphotyrosine | ||||
Sequence: Y |
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Gene expression databases
Organism-specific databases
Interaction
Subunit
Forms a ternary complex with NLRP1, composed of a DPP9 homodimer, one full-length NLRP1 protein, and one cleaved C-terminus of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, C-terminus) (PubMed:33731929, PubMed:33731932).
Forms a ternary complex with CARD8, composed of a DPP9 homodimer, one full-length NLRP1 protein, and one cleaved C-terminus of CARD8 (Caspase recruitment domain-containing protein 8, C-terminus) (PubMed:33731929, PubMed:34019797).
In the ternary complex, only one subunit of the DPP9 homodimer is bound to NLRP1 or CARD8 (PubMed:33731932, PubMed:34019797).
Binary interactions
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for region.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 1-20 | Disordered | ||||
Sequence: MATTGTPTADRGDAAATDDP |
Sequence similarities
Phylogenomic databases
Family and domain databases
Sequence & Isoforms
- Sequence statusComplete
This entry describes 3 isoforms produced by Alternative splicing.
Q86TI2-1
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name1
- SynonymsDPP9-S, Short
- Length863
- Mass (Da)98,263
- Last updated2005-06-07 v3
- Checksum40FE0B78E26CDED5
Q86TI2-2
- Name2
- SynonymsDPP9-L, Long
- NoteActive peptidase. Contains a nuclear localization signal at positions 2-9.
- Differences from canonical
- 1-1: M → MRKVKKLRLDKENTGSWRSFSLNSEGAERM
Q86TI2-4
- Name3
- Differences from canonical
- 832-858: Missing
Computationally mapped potential isoform sequences
There are 6 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A0A2R8YF65 | A0A2R8YF65_HUMAN | DPP9 | 782 | ||
M0R145 | M0R145_HUMAN | DPP9 | 77 | ||
M0R2A8 | M0R2A8_HUMAN | DPP9 | 518 | ||
M0R2G6 | M0R2G6_HUMAN | DPP9 | 140 | ||
M0QZ97 | M0QZ97_HUMAN | DPP9 | 62 | ||
A0A8V8TR99 | A0A8V8TR99_HUMAN | DPP9 | 857 |
Sequence caution
Features
Showing features for alternative sequence, sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_013865 | 1 | in isoform 2 | |||
Sequence: M → MRKVKKLRLDKENTGSWRSFSLNSEGAERM | ||||||
Sequence conflict | 204 | in Ref. 3; AAO73880/AAQ83119 | ||||
Sequence: I → N | ||||||
Sequence conflict | 461 | in Ref. 9; CAD39039 | ||||
Sequence: L → F | ||||||
Sequence conflict | 571 | in Ref. 5; BAC85150 | ||||
Sequence: C → W | ||||||
Sequence conflict | 709 | in Ref. 5; BAD18643 | ||||
Sequence: L → P | ||||||
Sequence conflict | 753 | in Ref. 5; BAB70784 | ||||
Sequence: G → C | ||||||
Alternative sequence | VSP_013869 | 832-858 | in isoform 3 | |||
Sequence: Missing |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF452102 EMBL· GenBank· DDBJ | AAL47179.1 EMBL· GenBank· DDBJ | mRNA | Different initiation | |
AY172660 EMBL· GenBank· DDBJ | AAO17262.1 EMBL· GenBank· DDBJ | mRNA | ||
AF542510 EMBL· GenBank· DDBJ | AAO73880.2 EMBL· GenBank· DDBJ | mRNA | Different initiation | |
AY374518 EMBL· GenBank· DDBJ | AAQ83119.1 EMBL· GenBank· DDBJ | mRNA | ||
DQ417928 EMBL· GenBank· DDBJ | ABD83624.1 EMBL· GenBank· DDBJ | mRNA | ||
AK054656 EMBL· GenBank· DDBJ | BAB70784.1 EMBL· GenBank· DDBJ | mRNA | Different initiation | |
AK075030 EMBL· GenBank· DDBJ | BAC11362.1 EMBL· GenBank· DDBJ | mRNA | Different initiation | |
AK122654 EMBL· GenBank· DDBJ | BAG53644.1 EMBL· GenBank· DDBJ | mRNA | ||
AK131100 EMBL· GenBank· DDBJ | BAC85150.1 EMBL· GenBank· DDBJ | mRNA | Sequence problems. | |
AK131499 EMBL· GenBank· DDBJ | BAD18643.1 EMBL· GenBank· DDBJ | mRNA | Sequence problems. | |
AC005594 EMBL· GenBank· DDBJ | AAC33801.1 EMBL· GenBank· DDBJ | Genomic DNA | Sequence problems. | |
AC005783 EMBL· GenBank· DDBJ | AAC62840.1 EMBL· GenBank· DDBJ | Genomic DNA | Sequence problems. | |
CH471139 EMBL· GenBank· DDBJ | EAW69199.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471139 EMBL· GenBank· DDBJ | EAW69201.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC000970 EMBL· GenBank· DDBJ | AAH00970.1 EMBL· GenBank· DDBJ | mRNA | ||
BC037948 EMBL· GenBank· DDBJ | AAH37948.1 EMBL· GenBank· DDBJ | mRNA | Different initiation | |
AL834376 EMBL· GenBank· DDBJ | CAD39039.3 EMBL· GenBank· DDBJ | mRNA | Frameshift | |
CR627380 EMBL· GenBank· DDBJ | CAH10477.1 EMBL· GenBank· DDBJ | mRNA |