UniProt functional annotation for Q8NB16



	UniProt functional annotation for Q8NB16

UniProt code: Q8NB16.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Pseudokinase that plays a key role in TNF-induced necroptosis, a programmed cell death process (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671). Does not have protein kinase activity (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671). Activated following phosphorylation by RIPK3, leading to homotrimerization, localization to the plasma membrane and execution of programmed necrosis characterized by calcium influx and plasma membrane damage (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671). In addition to TNF-induced necroptosis, necroptosis can also take place in the nucleus in response to orthomyxoviruses infection: following activation by ZBP1, MLKL is phosphorylated by RIPK3 in the nucleus, triggering disruption of the nuclear envelope and leakage of cellular DNA into the cytosol.following ZBP1 activation, which senses double-stranded Z-RNA structures, nuclear RIPK3 catalyzes phosphorylation and activation of MLKL, promoting disruption of the nuclear envelope and leakage of cellular DNA into the cytosol (By similarity). Binds to highly phosphorylated inositol phosphates such as inositolhexakisphosphate (InsP6) which is essential for its necroptotic function (PubMed:29883610). {ECO:0000250|UniProtKB:Q9D2Y4, ECO:0000269|PubMed:22265413, ECO:0000269|PubMed:22265414, ECO:0000269|PubMed:22421439, ECO:0000269|PubMed:24316671, ECO:0000269|PubMed:29883610}.

Activity regulation: Activated via binding to highly phosphorylated inositol phosphates such as inositolhexakisphosphate (InsP6) which mediates the release of an N-terminal auto-inhibitory region (PubMed:29883610). Activation requires not only RIPK3-dependent phosphorylation but also binding to highly phosphorylated inositol phosphates (PubMed:29883610). Inhibited by necrosulfonamide, a specific inhibitor of necroptosis that targets Cys-86 (PubMed:22265413). {ECO:0000269|PubMed:22265413, ECO:0000269|PubMed:29883610}.

Subunit: Homooligomer (PubMed:29883610). Homotrimer; forms homotrimers on necroptosis induction (PubMed:24316671). Upon TNF-induced necrosis, forms in complex with PGAM5, RIPK1 and RIPK3 (PubMed:22265414). Within this complex, may play a role in the proper targeting of RIPK1-RIPK3 to its downstream effector PGAM5 (PubMed:22265414). Interacts with RIPK3; the interaction is direct and promotes its phosphorylation and subsequent activation (PubMed:22265413, PubMed:22421439, PubMed:29883609). {ECO:0000269|PubMed:22265413, ECO:0000269|PubMed:22265414, ECO:0000269|PubMed:22421439, ECO:0000269|PubMed:24316671, ECO:0000269|PubMed:29883609, ECO:0000269|PubMed:29883610}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:24316671}. Cell membrane {ECO:0000269|PubMed:24316671, ECO:0000269|PubMed:29883610}. Nucleus {ECO:0000250|UniProtKB:Q9D2Y4}. Note=Localizes to the cytoplasm and translocates to the plasma membrane on necroptosis induction (PubMed:24316671). Localizes to the nucleus in response to orthomyxoviruses infection (By similarity). {ECO:0000250|UniProtKB:Q9D2Y4, ECO:0000269|PubMed:24316671}.

Domain: The protein kinase domain is catalytically inactive but contains an unusual pseudoactive site with an interaction between Lys- 230 and Gln-356 residues (By similarity). Upon phosphorylation by RIPK3, undergoes an active conformation (By similarity). {ECO:0000250|UniProtKB:Q9D2Y4}.

Domain: The coiled coil region 2 is responsible for homotrimerization. {ECO:0000269|PubMed:24316671}.

Ptm: Phosphorylation by RIPK3 induces a conformational switch that is required for necroptosis (PubMed:22265413). It also induces homotrimerization and localization to the plasma membrane (PubMed:22265413). {ECO:0000269|PubMed:22265413}.

Miscellaneous: Interaction with RIPK3 is species specific: human MLKL only interacts with human RIPK3 and not mouse RIPK3. {ECO:0000305|PubMed:22265413}.

Similarity: Belongs to the protein kinase superfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Pseudokinase that plays a key role in TNF-induced necroptosis, a programmed cell death process (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671). Does not have protein kinase activity (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671). Activated following phosphorylation by RIPK3, leading to homotrimerization, localization to the plasma membrane and execution of programmed necrosis characterized by calcium influx and plasma membrane damage (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671). In addition to TNF-induced necroptosis, necroptosis can also take place in the nucleus in response to orthomyxoviruses infection: following activation by ZBP1, MLKL is phosphorylated by RIPK3 in the nucleus, triggering disruption of the nuclear envelope and leakage of cellular DNA into the cytosol.following ZBP1 activation, which senses double-stranded Z-RNA structures, nuclear RIPK3 catalyzes phosphorylation and activation of MLKL, promoting disruption of the nuclear envelope and leakage of cellular DNA into the cytosol (By similarity). Binds to highly phosphorylated inositol phosphates such as inositolhexakisphosphate (InsP6) which is essential for its necroptotic function (PubMed:29883610). {ECO:0000250\|UniProtKB:Q9D2Y4, ECO:0000269\|PubMed:22265413, ECO:0000269\|PubMed:22265414, ECO:0000269\|PubMed:22421439, ECO:0000269\|PubMed:24316671, ECO:0000269\|PubMed:29883610}.


Activity regulation:		Activated via binding to highly phosphorylated inositol phosphates such as inositolhexakisphosphate (InsP6) which mediates the release of an N-terminal auto-inhibitory region (PubMed:29883610). Activation requires not only RIPK3-dependent phosphorylation but also binding to highly phosphorylated inositol phosphates (PubMed:29883610). Inhibited by necrosulfonamide, a specific inhibitor of necroptosis that targets Cys-86 (PubMed:22265413). {ECO:0000269\|PubMed:22265413, ECO:0000269\|PubMed:29883610}.
Subunit:		Homooligomer (PubMed:29883610). Homotrimer; forms homotrimers on necroptosis induction (PubMed:24316671). Upon TNF-induced necrosis, forms in complex with PGAM5, RIPK1 and RIPK3 (PubMed:22265414). Within this complex, may play a role in the proper targeting of RIPK1-RIPK3 to its downstream effector PGAM5 (PubMed:22265414). Interacts with RIPK3; the interaction is direct and promotes its phosphorylation and subsequent activation (PubMed:22265413, PubMed:22421439, PubMed:29883609). {ECO:0000269\|PubMed:22265413, ECO:0000269\|PubMed:22265414, ECO:0000269\|PubMed:22421439, ECO:0000269\|PubMed:24316671, ECO:0000269\|PubMed:29883609, ECO:0000269\|PubMed:29883610}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:24316671}. Cell membrane {ECO:0000269\|PubMed:24316671, ECO:0000269\|PubMed:29883610}. Nucleus {ECO:0000250\|UniProtKB:Q9D2Y4}. Note=Localizes to the cytoplasm and translocates to the plasma membrane on necroptosis induction (PubMed:24316671). Localizes to the nucleus in response to orthomyxoviruses infection (By similarity). {ECO:0000250\|UniProtKB:Q9D2Y4, ECO:0000269\|PubMed:24316671}.
Domain:		The protein kinase domain is catalytically inactive but contains an unusual pseudoactive site with an interaction between Lys- 230 and Gln-356 residues (By similarity). Upon phosphorylation by RIPK3, undergoes an active conformation (By similarity). {ECO:0000250\|UniProtKB:Q9D2Y4}.
Domain:		The coiled coil region 2 is responsible for homotrimerization. {ECO:0000269\|PubMed:24316671}.
Ptm:		Phosphorylation by RIPK3 induces a conformational switch that is required for necroptosis (PubMed:22265413). It also induces homotrimerization and localization to the plasma membrane (PubMed:22265413). {ECO:0000269\|PubMed:22265413}.
Miscellaneous:		Interaction with RIPK3 is species specific: human MLKL only interacts with human RIPK3 and not mouse RIPK3. {ECO:0000305\|PubMed:22265413}.
Similarity:		Belongs to the protein kinase superfamily. {ECO:0000305}.