Q9D2Y4
SS
Gene name |
Mlkl |
Protein name |
Mixed lineage kinase domain-like protein |
Names |
|
Species |
Mus musculus (Mouse) |
KEGG Pathway |
mmu:74568 |
EC number |
|
Protein Class |
|
Descriptions
MLKL (mixed-lineage kinase domain-like protein) is a key effector in necroptosis, consisting of two domains connected by brace helices. The N-terminal executioner domain forms a four-helix bundle crucial for its function. MLKL’s autoinhibited state is maintained by the brace helix α6, which interacts with the four-helix bundle. This interaction prevents MLKL from oligomerizing and integrating into the plasma membrane, which is necessary for necroptosis. Upon phosphorylation by RIPK3, the autoinhibitory brace helix α6 detaches, leading to MLKL oligomerization and membrane integration, resulting in cell death. Covalent inhibitors targeting MLKL can stabilize its autoinhibited state by reinforcing the interaction between brace helix α6 and the four-helix bundle, thus preventing necroptosis.
Autoinhibitory domains (AIDs)
Target domain |
2-144 (N-terminal executioner domain) |
Relief mechanism |
PTM |
Assay |
|
Accessory elements
No accessory elements
Autoinhibited structure
Activated structure
4 structures for Q9D2Y4
| Entry ID | Method | Resolution | Chain | Position | Source |
|---|---|---|---|---|---|
| 4BTF | X-ray | 260 A | A | 1-472 | PDB |
| 4M68 | X-ray | 170 A | A | 182-472 | PDB |
| 4M69 | X-ray | 250 A | B | 182-472 | PDB |
| AF-Q9D2Y4-F1 | Predicted | AlphaFoldDB |
29 variants for Q9D2Y4
| Variant ID(s) | Position | Change | Description | Diseaes Association | Provenance |
|---|---|---|---|---|---|
| rs31297999 | 16 | E>D | No | EVA | |
| rs3412796698 | 120 | W>R | No | EVA | |
| rs31296318 | 148 | M>T | No | EVA | |
| rs236265597 | 188 | K>R | No | EVA | |
| rs3389014387 | 193 | P>H | No | EVA | |
| rs3399134453 | 194 | P>Q | No | EVA | |
| rs3389012063 | 226 | A>T | No | EVA | |
| rs246205681 | 234 | F>L | No | EVA | |
| rs234554142 | 254 | I>V | No | EVA | |
| rs3389018359 | 257 | I>F | No | EVA | |
| rs3389006064 | 264 | K>N | No | EVA | |
| rs3399715504 | 267 | E>Q | No | EVA | |
| rs3399680238 | 268 | F>Y | No | EVA | |
| rs3389014342 | 274 | Y>N | No | EVA | |
| rs3399134457 | 275 | C>* | No | EVA | |
| rs3388982811 | 278 | G>A | No | EVA | |
| rs3388993286 | 307 | Y>C | No | EVA | |
| rs3389011997 | 312 | S>A | No | EVA | |
| rs3389006004 | 328 | G>E | No | EVA | |
| rs3389014348 | 365 | S>F | No | EVA | |
| rs3388993305 | 375 | L>H | No | EVA | |
| rs232724778 | 375 | L>I | No | EVA | |
| rs3388988180 | 404 | S>Y | No | EVA | |
| rs3389006047 | 428 | L>F | No | EVA | |
| rs3389012911 | 436 | R>P | No | EVA | |
| rs3388993342 | 454 | R>K | No | EVA | |
| rs3389011882 | 460 | R>* | No | EVA | |
| rs226375416 | 468 | T>K | No | EVA | |
| rs3388963756 | 471 | K>Q | No | EVA |
No associated diseases with Q9D2Y4
Functions
5 GO annotations of cellular component
| Name | Definition |
|---|---|
| cell junction | A cellular component that forms a specialized region of connection between two or more cells, or between a cell and the extracellular matrix, or between two membrane-bound components of a cell, such as flagella. |
| cytoplasm | The contents of a cell excluding the plasma membrane and nucleus, but including other subcellular structures. |
| cytosol | The part of the cytoplasm that does not contain organelles but which does contain other particulate matter, such as protein complexes. |
| nucleus | A membrane-bounded organelle of eukaryotic cells in which chromosomes are housed and replicated. In most cells, the nucleus contains all of the cell's chromosomes except the organellar chromosomes, and is the site of RNA synthesis and processing. In some species, or in specialized cell types, RNA metabolism or DNA replication may be absent. |
| plasma membrane | The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins. |
3 GO annotations of molecular function
| Name | Definition |
|---|---|
| ATP binding | Binding to ATP, adenosine 5'-triphosphate, a universally important coenzyme and enzyme regulator. |
| protein kinase binding | Binding to a protein kinase, any enzyme that catalyzes the transfer of a phosphate group, usually from ATP, to a protein substrate. |
| protein-containing complex binding | Binding to a macromolecular complex. |
6 GO annotations of biological process
| Name | Definition |
|---|---|
| cell surface receptor signaling pathway | The series of molecular signals initiated by activation of a receptor on the surface of a cell. The pathway begins with binding of an extracellular ligand to a cell surface receptor, or for receptors that signal in the absence of a ligand, by ligand-withdrawal or the activity of a constitutively active receptor. The pathway ends with regulation of a downstream cellular process, e.g. transcription. |
| defense response to virus | Reactions triggered in response to the presence of a virus that act to protect the cell or organism. |
| execution phase of necroptosis | A stage of the necroptotic process that starts after a necroptotic signal has been relayed to the execution machinery. Key steps of the execution phase are swelling of organelles, minor ultrastructural modifications of the nucleus (specifically, dilatation of the nuclear membrane and condensation of chromatin into small, irregular, circumscribed patches) and increased cell volume (oncosis), culminating in the disruption of the plasma membrane and subsequent loss of intracellular contents. The execution phase ends when the cell has died. |
| necroptotic process | A programmed necrotic cell death process which begins when a cell receives a signal (e.g. a ligand binding to a death receptor or to a Toll-like receptor), and proceeds through a series of biochemical events (signaling pathways), characterized by activation of receptor-interacting serine/threonine-protein kinase 1 and/or 3 (RIPK1/3, also called RIP1/3) and by critical dependence on mixed lineage kinase domain-like (MLKL), and which typically lead to common morphological features of necrotic cell death. The process ends when the cell has died. The process is divided into a signaling phase, and an execution phase, which is triggered by the former. |
| necroptotic signaling pathway | The series of molecular signals which triggers the necroptotic death of a cell. The pathway starts with reception of a signal, is characterized by activation of receptor-interacting serine/threonine-protein kinase 1 and/or 3 (RIPK1/3, also called RIP1/3), and ends when the execution phase of necroptosis is triggered. |
| protein homotrimerization | The formation of a protein homotrimer, a macromolecular structure consisting of three noncovalently associated identical subunits. |
43 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 |
| P11346 | Raf | Raf homolog serine/threonine-protein kinase Raf | Drosophila melanogaster (Fruit fly) | PR |
| O43353 | RIPK2 | Receptor-interacting serine/threonine-protein kinase 2 | Homo sapiens (Human) | PR |
| Q02779 | MAP3K10 | Mitogen-activated protein kinase kinase kinase 10 | Homo sapiens (Human) | SS |
| Q16584 | MAP3K11 | Mitogen-activated protein kinase kinase kinase 11 | Homo sapiens (Human) | EV |
| P00540 | MOS | Proto-oncogene serine/threonine-protein kinase mos | Homo sapiens (Human) | PR |
| Q5TCX8 | MAP3K21 | Mitogen-activated protein kinase kinase kinase 21 | 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 |
| Q8NB16 | MLKL | Mixed lineage kinase domain-like protein | Homo sapiens (Human) | EV |
| 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 |
| Q66L42 | Map3k10 | Mitogen-activated protein kinase kinase kinase 10 | Mus musculus (Mouse) | SS |
| Q3U1V8 | Map3k9 | Mitogen-activated protein kinase kinase kinase 9 | Mus musculus (Mouse) | SS |
| Q8VDG6 | Map3k21 | Mitogen-activated protein kinase kinase kinase 21 | Mus musculus (Mouse) | PR |
| Q80XI6 | Map3k11 | Mitogen-activated protein kinase kinase kinase 11 | 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 |
| P04627 | Araf | Serine/threonine-protein kinase A-Raf | Mus musculus (Mouse) | PR |
| P28028 | Braf | Serine/threonine-protein kinase B-raf | Mus musculus (Mouse) | SS |
| P0C8E4 | Map3k7 | Mitogen-activated protein kinase kinase kinase 7 | Rattus norvegicus (Rat) | SS |
| Q66HA1 | Map3k11 | Mitogen-activated protein kinase kinase kinase 11 | Rattus norvegicus (Rat) | PR |
| 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 |
| Q9TZM3 | lrk-1 | Leucine-rich repeat serine/threonine-protein kinase 1 | Caenorhabditis elegans | SS |
| Q07292 | lin-45 | Raf homolog serine/threonine-protein kinase | Caenorhabditis elegans | PR |
| 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 |
| MDKLGQIIKL | GQLIYEQCEK | MKYCRKQCQR | LGNRVHGLLQ | PLQRLQAQGK | KNLPDDITAA |
| 70 | 80 | 90 | 100 | 110 | 120 |
| LGRFDEVLKE | ANQQIEKFSK | KSHIWKFVSV | GNDKILFHEV | NEKLRDVWEE | LLLLLQVYHW |
| 130 | 140 | 150 | 160 | 170 | 180 |
| NTVSDVSQPA | SWQQEDRQDA | EEDGNENMKV | ILMQLQISVE | EINKTLKQCS | LKPTQEIPQD |
| 190 | 200 | 210 | 220 | 230 | 240 |
| LQIKEIPKEH | LGPPWTKLKT | SKMSTIYRGE | YHRSPVTIKV | FNNPQAESVG | IVRFTFNDEI |
| 250 | 260 | 270 | 280 | 290 | 300 |
| KTMKKFDSPN | ILRIFGICID | QTVKPPEFSI | VMEYCELGTL | RELLDREKDL | TMSVRSLLVL |
| 310 | 320 | 330 | 340 | 350 | 360 |
| RAARGLYRLH | HSETLHRNIS | SSSFLVAGGY | QVKLAGFELS | KTQNSISRTA | KSTKAERSSS |
| 370 | 380 | 390 | 400 | 410 | 420 |
| TIYVSPERLK | NPFCLYDIKA | EIYSFGIVLW | EIATGKIPFE | GCDSKKIREL | VAEDKKQEPV |
| 430 | 440 | 450 | 460 | 470 | |
| GQDCPELLRE | IINECRAHEP | SQRPSVDGRS | LSGRERILER | LSAVEESTDK | KV |