Receptor-interacting serine/threonine-protein kinase 3 - Q9Z2P5 (RIPK3_RAT)

 

Protein Feature View of PDB entries mapped to a UniProtKB sequence  

 
Function
Serine/threonine-protein kinase that activates necroptosis and apoptosis, two parallel forms of cell death. Necroptosis, a programmed cell death process in response to death-inducing TNF-alpha family members, is triggered by RIPK3 following activation by ZBP1. Activated RIPK3 forms a necrosis-inducing complex and mediates phosphorylation of MLKL, promoting MLKL localization to the plasma membrane and execution of programmed necrosis characterized by calcium influx and plasma membrane damage. In addition to TNF-induced necroptosis, necroptosis can also take place in the nucleus in response to orthomyxoviruses infection: 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. Also regulates apoptosis: apoptosis depends on RIPK1, FADD and CASP8, and is independent of MLKL and RIPK3 kinase activity (By similarity). Phosphorylates RIPK1: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation (By similarity). In some cell types, also able to restrict viral replication by promoting cell death-independent responses. In response to flavivirus infection in neurons, promotes a cell death-independent pathway that restricts viral replication: together with ZBP1, promotes a death-independent transcriptional program that modifies the cellular metabolism via up-regulation expression of the enzyme ACOD1/IRG1 and production of the metabolite itaconate. Itaconate inhibits the activity of succinate dehydrogenase, generating a metabolic state in neurons that suppresses replication of viral genomes (By similarity). RIPK3 binds to and enhances the activity of three metabolic enzymes: GLUL, GLUD1, and PYGL. These metabolic enzymes may eventually stimulate the tricarboxylic acid cycle and oxidative phosphorylation, which could result in enhanced ROS production (By similarity). UniProt
Catalytic Activity
ATP + L-threonyl-[protein] = ADP + H+ + O-phospho-L-threonyl-[protein] UniProt
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Subunit Structure
Interacts (via RIP homotypic interaction motif) with RIPK1 (via RIP homotypic interaction motif); this interaction induces RIPK1 phosphorylation and formation of a RIPK1-RIPK3 necrosis-inducing complex. Interacts with MLKL; the interaction is direct and triggers necroptosis. Interacts with ZBP1 (via RIP homotypic interaction motif); interaction with ZBP1 activates RIPK3, triggering necroptosis (By similarity). Upon TNF-induced necrosis, the RIPK1-RIPK3 dimer further interacts with PGAM5 and MLKL; the formation of this complex leads to PGAM5 phosphorylation and increase in PGAM5 phosphatase activity. Binds TRAF2 and is recruited to the TNFR-1 signaling complex. Interacts with PYGL, GLUL and GLUD1; these interactions result in activation of these metabolic enzymes. Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4. Interacts with ARHGEF2 (By similarity). Interacts with PELI1 (via atypical FHA domain); the phosphorylated form at Thr-185 binds preferentially to PELI1 (By similarity). Interacts with BUB1B, TRAF2 and STUB1 (By similarity). UniProt
Domain
The RIP homotypic interaction motif (RHIM) mediates interaction with the RHIM motif of RIPK1. Both motifs form a hetero-amyloid serpentine fold, stabilized by hydrophobic packing and featuring an unusual Cys-Ser ladder of alternating Ser (from RIPK1) and Cys (from RIPK3). UniProt
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Data in green originates from UniProtKB  
Variation data (sourced from UniProt) shows non-genetic variation from the ExPASy   and dbSNP   websites.
Data in yellow originates from Pfam  , by interacting with the HMMER3 web site  
Data in purple originates from Phosphosite  .
Data in orange originates from the SCOP   (version 1.75) and SCOPe   (version 2.04) classifications.
Data in grey has been calculated using BioJava  . Protein disorder predictions are based on JRONN (Troshin, P. and Barton, G. J. unpublished), a Java implementation of RONN  
  • Red: potentially disorderd region
  • Blue: probably ordered region.
Hydropathy has been calculated using a sliding window of 15 residues and summing up scores from standard hydrophobicity tables.
  • Red: hydrophobic
  • Blue: hydrophilic.
Data in lilac represent the genomic exon structure projected onto the UniProt sequence.
Data in blue originates from PDB
  • Secstruc: Secondary structure projected from representative PDB entries onto the UniProt sequence.
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Data in red indicates combined ranges of Homology Models from the SWISS-MODEL Repository  
The PDB to UniProt mapping is based on the data provided by the EBI SIFTS project. See also Velankar et al., Nucleic Acids Research 33, D262-265 (2005).
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