Q8VDG6
Gene name |
Map3k21 (Kiaa1804, Mlk4) |
Protein name |
Mitogen-activated protein kinase kinase kinase 21 |
Names |
Mitogen-activated protein kinase kinase kinase MLK4, Mixed lineage kinase 4 |
Species |
Mus musculus (Mouse) |
KEGG Pathway |
mmu:234878 |
EC number |
2.7.11.25: Protein-serine/threonine kinases |
Protein Class |
|
Descriptions
(Annotation based on sequence homology with Q16584)
Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAPKKK) that activates the c-Jun N-terminal kinase (JNK) pathway through the dual phosphorylation of mitogen-activated protein kinase kinases 4/7 (MKK4/7). The catalytic domain of MLK3 is flanked by an N-terminal SH3 domain and a centrally located zipper and Cdc42/Rac-interactive binding (CRIB) motif. Zipper-mediated homo-oligomerization is required for full activity of MLK3, proper substrate phosphorylation, and activation of the JNK pathway. MLK3 is autoinhibited through an interaction between its SH3 domain and a proline-containing sequence between the zipper and the CRIB motif. Activated forms of the small GTPases Cdc42 and Rac interact with MLK3 in a CRIB motif-dependent manner to increase the autophosphorylation of MLK3 and substrate phosphorylation activity and to potentiate MLK3-induced activation of JNK. Activated Cdc42 translocates MLK3 to membranes and induces activation loop phosphorylation of MLK3.
Autoinhibitory domains (AIDs)
Target domain |
|
Relief mechanism |
|
Assay |
cis-regPred |
Accessory elements
272-293 (Activation loop)
Target domain |
110-390 (Protein kinase domain) |
Relief mechanism |
|
Assay |
|
Autoinhibited structure
Activated structure
1 structures for Q8VDG6
| Entry ID | Method | Resolution | Chain | Position | Source |
|---|---|---|---|---|---|
| AF-Q8VDG6-F1 | Predicted | AlphaFoldDB |
54 variants for Q8VDG6
| Variant ID(s) | Position | Change | Description | Diseaes Association | Provenance |
|---|---|---|---|---|---|
| rs3399730705 | 52 | E>* | No | EVA | |
| rs3399813165 | 52 | E>A | No | EVA | |
| rs3399221371 | 130 | Q>H | No | EVA | |
| rs3399847309 | 130 | Q>P | No | EVA | |
| rs3399241842 | 131 | G>C | No | EVA | |
| rs1134814625 | 219 | Q>K | No | EVA | |
| rs3389018292 | 298 | E>D | No | EVA | |
| rs3389021707 | 345 | L>P | No | EVA | |
| rs3399221347 | 449 | Q>L | No | EVA | |
| rs3399834500 | 450 | Q>L | No | EVA | |
| rs3399713569 | 453 | E>A | No | EVA | |
| rs3389001460 | 510 | Q>* | No | EVA | |
| rs3389008346 | 600 | G>D | No | EVA | |
| rs3412732370 | 600 | G>S | No | EVA | |
| rs3389008365 | 609 | I>K | No | EVA | |
| rs3389028011 | 616 | P>A | No | EVA | |
| rs3388997150 | 629 | E>D | No | EVA | |
| rs32047967 | 636 | E>D | No | EVA | |
| rs238461716 | 640 | H>Y | No | EVA | |
| rs32047970 | 650 | G>C | No | EVA | |
| rs6154691 | 683 | V>M | No | EVA | |
| rs247240072 | 686 | V>M | No | EVA | |
| rs257362226 | 688 | A>V | No | EVA | |
| rs3388971544 | 702 | C>F | No | EVA | |
| rs3389024288 | 711 | L>V | No | EVA | |
| rs238129913 | 724 | P>T | No | EVA | |
| rs6155746 | 733 | K>E | No | EVA | |
| rs6155813 | 747 | S>A | No | EVA | |
| rs3388971566 | 755 | Q>H | No | EVA | |
| rs6168893 | 764 | G>D | No | EVA | |
| rs232900565 | 767 | T>M | No | EVA | |
| rs245089455 | 773 | A>T | No | EVA | |
| rs3389020175 | 775 | S>R | No | EVA | |
| rs3399813130 | 778 | S>P | No | EVA | |
| rs6168998 | 786 | C>S | No | EVA | |
| rs6169014 | 790 | A>D | No | EVA | |
| rs3389027094 | 799 | N>Y | No | EVA | |
| rs242755995 | 801 | R>Q | No | EVA | |
| rs6169484 | 803 | L>S | No | EVA | |
| rs579794282 | 808 | T>M | No | EVA | |
| rs32049866 | 817 | A>T | No | EVA | |
| rs32049871 | 821 | G>S | No | EVA | |
| rs3388997135 | 824 | L>I | No | EVA | |
| rs255467682 | 848 | T>S | No | EVA | |
| rs222855672 | 862 | G>E | No | EVA | |
| rs238194370 | 864 | H>Y | No | EVA | |
| rs3389001442 | 895 | Q>P | No | EVA | |
| rs3389027093 | 907 | P>S | No | EVA | |
| rs32050789 | 929 | V>L | No | EVA | |
| rs32050792 | 938 | V>A | No | EVA | |
| rs3389018505 | 940 | D>V | No | EVA | |
| rs3389027096 | 960 | C>Y | No | EVA | |
| rs32051725 | 974 | K>N | No | EVA | |
| rs3389020156 | 984 | V>M | No | EVA |
No associated diseases with Q8VDG6
5 regional properties for Q8VDG6
| Type | Name | Position | InterPro Accession |
|---|---|---|---|
| domain | Protein kinase domain | 110 - 390 | IPR000719 |
| domain | Serine-threonine/tyrosine-protein kinase, catalytic domain | 110 - 382 | IPR001245 |
| domain | SH3 domain | 24 - 88 | IPR001452 |
| active_site | Serine/threonine-protein kinase, active site | 243 - 255 | IPR008271 |
| binding_site | Protein kinase, ATP binding site | 116 - 137 | IPR017441 |
Functions
| Description | ||
|---|---|---|
| EC Number | 2.7.11.25 | Protein-serine/threonine kinases |
| Subcellular Localization |
|
|
| PANTHER Family | ||
| PANTHER Subfamily | ||
| PANTHER Protein Class | ||
| PANTHER Pathway Category | No pathway information available | |
No GO annotations of cellular component
| Name | Definition |
|---|---|
| No GO annotations for cellular component |
4 GO annotations of molecular function
| Name | Definition |
|---|---|
| ATP binding | Binding to ATP, adenosine 5'-triphosphate, a universally important coenzyme and enzyme regulator. |
| JUN kinase kinase kinase activity | Catalysis of the reaction: JNKK + ATP = JNKK phosphate + ADP. This reaction is the phosphorylation and activation of JUN kinase kinases (JNKKs). |
| protein serine kinase activity | Catalysis of the reactions: ATP + protein serine = ADP + protein serine phosphate. |
| protein serine/threonine kinase activity | Catalysis of the reactions: ATP + protein serine = ADP + protein serine phosphate, and ATP + protein threonine = ADP + protein threonine phosphate. |
1 GO annotations of biological process
| Name | Definition |
|---|---|
| protein phosphorylation | The process of introducing a phosphate group on to a protein. |
41 homologous proteins in AiPD
| UniProt AC | Gene Name | Protein Name | Species | Evidence Code |
|---|---|---|---|---|
| A2VDU3 | MAP3K7 | Mitogen-activated protein kinase kinase kinase 7 | Bos taurus (Bovine) | SS |
| Q4TVR5 | DSTYK | Dual serine/threonine and tyrosine protein kinase | Bos taurus (Bovine) | PR |
| Q3SZJ2 | RIPK2 | Receptor-interacting serine/threonine-protein kinase 2 | Bos taurus (Bovine) | PR |
| Q6XUX0 | DSTYK | Dual serine/threonine and tyrosine protein kinase | Gallus gallus (Chicken) | PR |
| P83104 | Takl1 | Putative mitogen-activated protein kinase kinase kinase 7-like | Drosophila melanogaster (Fruit fly) | PR |
| Q95UN8 | slpr | Mitogen-activated protein kinase kinase kinase | Drosophila melanogaster (Fruit fly) | EV |
| O43353 | RIPK2 | Receptor-interacting serine/threonine-protein kinase 2 | Homo sapiens (Human) | PR |
| Q8NB16 | MLKL | Mixed lineage kinase domain-like protein | Homo sapiens (Human) | EV |
| P00540 | MOS | Proto-oncogene serine/threonine-protein kinase mos | Homo sapiens (Human) | PR |
| Q6XUX3 | DSTYK | Dual serine/threonine and tyrosine protein kinase | Homo sapiens (Human) | PR |
| O43318 | MAP3K7 | Mitogen-activated protein kinase kinase kinase 7 | Homo sapiens (Human) | SS |
| Q9NYL2 | MAP3K20 | Mitogen-activated protein kinase kinase kinase 20 | Homo sapiens (Human) | PR |
| Q38SD2 | LRRK1 | Leucine-rich repeat serine/threonine-protein kinase 1 | Homo sapiens (Human) | EV |
| P80192 | MAP3K9 | Mitogen-activated protein kinase kinase kinase 9 | Homo sapiens (Human) | SS |
| Q16584 | MAP3K11 | Mitogen-activated protein kinase kinase kinase 11 | Homo sapiens (Human) | EV |
| Q5TCX8 | MAP3K21 | Mitogen-activated protein kinase kinase kinase 21 | Homo sapiens (Human) | PR |
| Q02779 | MAP3K10 | Mitogen-activated protein kinase kinase kinase 10 | Homo sapiens (Human) | SS |
| Q62073 | Map3k7 | Mitogen-activated protein kinase kinase kinase 7 | Mus musculus (Mouse) | EV |
| P00536 | Mos | Proto-oncogene serine/threonine-protein kinase mos | Mus musculus (Mouse) | PR |
| P58801 | Ripk2 | Receptor-interacting serine/threonine-protein kinase 2 | Mus musculus (Mouse) | PR |
| Q3U1V8 | Map3k9 | Mitogen-activated protein kinase kinase kinase 9 | Mus musculus (Mouse) | SS |
| Q66L42 | Map3k10 | Mitogen-activated protein kinase kinase kinase 10 | Mus musculus (Mouse) | SS |
| Q80XI6 | Map3k11 | Mitogen-activated protein kinase kinase kinase 11 | Mus musculus (Mouse) | PR |
| P04627 | Araf | Serine/threonine-protein kinase A-Raf | Mus musculus (Mouse) | PR |
| O55222 | Ilk | Integrin-linked protein kinase | Mus musculus (Mouse) | PR |
| Q9ESL4 | Map3k20 | Mitogen-activated protein kinase kinase kinase 20 | Mus musculus (Mouse) | PR |
| Q99N57 | Raf1 | RAF proto-oncogene serine/threonine-protein kinase | Mus musculus (Mouse) | SS |
| P28028 | Braf | Serine/threonine-protein kinase B-raf | Mus musculus (Mouse) | SS |
| Q9D2Y4 | Mlkl | Mixed lineage kinase domain-like protein | Mus musculus (Mouse) | SS |
| P0C8E4 | Map3k7 | Mitogen-activated protein kinase kinase kinase 7 | Rattus norvegicus (Rat) | SS |
| D3ZG83 | Map3k10 | Mitogen-activated protein kinase kinase kinase 10 | Rattus norvegicus (Rat) | SS |
| P00539 | Mos | Proto-oncogene serine/threonine-protein kinase mos | Rattus norvegicus (Rat) | PR |
| Q66HA1 | Map3k11 | Mitogen-activated protein kinase kinase kinase 11 | Rattus norvegicus (Rat) | PR |
| Q9TZM3 | lrk-1 | Leucine-rich repeat serine/threonine-protein kinase 1 | Caenorhabditis elegans | SS |
| Q9FPR3 | EDR1 | Serine/threonine-protein kinase EDR1 | Arabidopsis thaliana (Mouse-ear cress) | PR |
| Q2MHE4 | HT1 | Serine/threonine/tyrosine-protein kinase HT1 | Arabidopsis thaliana (Mouse-ear cress) | PR |
| O22558 | STY8 | Serine/threonine-protein kinase STY8 | Arabidopsis thaliana (Mouse-ear cress) | PR |
| Q8RWL6 | STY17 | Serine/threonine-protein kinase STY17 | Arabidopsis thaliana (Mouse-ear cress) | PR |
| F4JTP5 | STY46 | Serine/threonine-protein kinase STY46 | Arabidopsis thaliana (Mouse-ear cress) | PR |
| Q05609 | CTR1 | Serine/threonine-protein kinase CTR1 | Arabidopsis thaliana (Mouse-ear cress) | PR |
| Q67E00 | dstyk | Dual serine/threonine and tyrosine protein kinase | Xenopus tropicalis (Western clawed frog) (Silurana tropicalis) | PR |
| 10 | 20 | 30 | 40 | 50 | 60 |
| MALPVAEGTA | DTPLSPARDD | SGSTSSGMWA | ALYDYEARGE | DELSLRRGQL | VEVLSQDAAV |
| 70 | 80 | 90 | 100 | 110 | 120 |
| SGDEGWWAGQ | VQRRLGIFPA | SYVAPCGPVP | PPAPPPPRPC | SPVHVDFERL | ELKELIGAGG |
| 130 | 140 | 150 | 160 | 170 | 180 |
| FGQVYRATWQ | GQEVAVKAAR | RDPEQDAAAA | AESVRREARL | FAMLRHPNII | QLRGVCLRQP |
| 190 | 200 | 210 | 220 | 230 | 240 |
| HLCLVLEFAR | GGALNRALAA | AASDPRAPGP | RRARRIPPQV | LVNWAVQIAR | GMLYLHEEAV |
| 250 | 260 | 270 | 280 | 290 | 300 |
| VPILHRDLKS | SNILLLEKIE | HDDICNKTLK | ITDFGLAREW | HRTTRMSAAG | TYAWMAPEVI |
| 310 | 320 | 330 | 340 | 350 | 360 |
| RSSLFSKGSD | IWSYGVLLWE | LLTGEVPYRG | IDGLAVAYGV | AVNKLTLPIP | STCPEPFAKL |
| 370 | 380 | 390 | 400 | 410 | 420 |
| MKECWEQDPH | IRPSFALILQ | QLTAIEEAVL | TNMPQESFHS | MQEDWKLEIQ | QMFSELRTKE |
| 430 | 440 | 450 | 460 | 470 | 480 |
| KELRSREEEL | SRAALQQKSQ | ELLLRRREQQ | LAEREIDVLE | RELNVLIFQL | SQEAPHVKKR |
| 490 | 500 | 510 | 520 | 530 | 540 |
| KGRFRRGRLR | LKDGHRISLP | SDFQHKITVQ | ASPTLDKRRS | SDSGLCSPPG | SPLMLPRLRA |
| 550 | 560 | 570 | 580 | 590 | 600 |
| IQLTSDENNK | TRGRNMVFRQ | EDFEDVKRSF | KKKGCTWGPS | SVQTKERPEG | RERVRPLSDG |
| 610 | 620 | 630 | 640 | 650 | 660 |
| NSPWSSLLIK | SQKTTPLASL | FVDQPGSCEE | QKLVPEGLEH | RKPKQTKFPG | QAHVGLPLCK |
| 670 | 680 | 690 | 700 | 710 | 720 |
| DSQREDSSEA | ESREEGSPKG | SPVNNVGAPM | LRKKTESALC | ECGMLLASMA | LGLDVRKLHG |
| 730 | 740 | 750 | 760 | 770 | 780 |
| AQAPAKPSPK | MEKKEEGALQ | PASRCQSSPS | SLLRQPSAGR | APSGGSTLLL | PSAPSHSSKS |
| 790 | 800 | 810 | 820 | 830 | 840 |
| SLSMKCLLQA | GKEESSLGNA | RDLCGPTTLT | PDPGSAAPES | GCELIPGLRP | KTDYGVLRSM |
| 850 | 860 | 870 | 880 | 890 | 900 |
| PHAILEQTGE | RLPGCAIVGD | KGCHHMQMGS | EETPLWLQSA | PEDSGLPHSP | SPGPQRDLAS |
| 910 | 920 | 930 | 940 | 950 | 960 |
| QASLVKPEGV | LGECQACPAL | PQRPHTASVR | TTSPPTWVCD | KDHQVPALAC | LLGAQERSRC |
| 970 | 980 | 990 | 1000 | ||
| QTPSLLDASI | EGQKKDCAMP | LCRVKSVMCQ | PSIYALEKDF | LT |