Publication: The C2 domain of Tollip, a Toll-like receptor signalling regulator, exhibits broad preference for phosphoinositides
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Issued Date
2011
Resource Type
File Type
application/pdf
ISSN
2646021
Other identifier(s)
2-s2.0-79954486751
Rights Holder(s)
มหาวิทยาลัยศรีนครินทรวิโรฒ
Bibliographic Citation
Biochemical Journal. Vol 435, No.3 (2011), p.597-608
Suggested Citation
Ankem G., Mitra S., Sun F., Moreno A.C., Chutvirasakul B., Azurmendi H.F., Li L., Capelluto D.G.S. The C2 domain of Tollip, a Toll-like receptor signalling regulator, exhibits broad preference for phosphoinositides. Biochemical Journal. Vol 435, No.3 (2011), p.597-608. doi:10.1042/BJ20102160 Retrieved from: https://hdl.handle.net/20.500.14740/7339
Abstract
TLRs (Toll-like receptors) provide a mechanism for host defence immune responses. Activated TLRs lead to the recruitment of adaptor proteins to their cytosolic tails, which in turn promote the activation of IRAKs (interleukin-1 receptor-associated kinases). IRAKs act upon their transcription factor targets to influence the expression of genes involved in the immune response. Tollip (Toll-interacting protein) modulates IRAK function in the TLR signalling pathway. Tollip is multimodular, with a conserved C2 domain of unknown function. We found that the Tollip C2 domain preferentially interacts with phosphoinositides, most notably with PtdIns3P (phosphatidylinositol 3-phosphate) and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate), in a Ca2+-independent manner. However, NMR analysis demonstrates that the Tollip C2 domain binds Ca2+, which may be required to target the membrane interface. NMR and lipid - protein overlay analyses suggest that PtdIns3P and PtdIns(4,5)P2 share interacting residues in the protein. Kinetic studies reveal that the C2 domain reversibly binds PtdIns3P and PtdIns(4,5)P2, with affinity values in the low micromolar range. Mutational analysis identifies key PtdIns3P- and PtdIns(4,5)P 2-binding conserved basic residues in the protein. Our findings suggest that basic residues of the C2 domain mediate membrane targeting of Tollip by interaction with phosphoinositides, which contribute to the observed partition of the protein in different subcellular compartments. © The Authors Journal compilation © 2011 Biochemical Society.
Subject(s)
Calcium ion
Interleukin 1 receptor associated kinase
Liposome
Phosphatidylinositol 3 phosphate
Phosphatidylinositol 4,5 bisphosphate
Synaptotagmin
Toll like receptor
Tollip
Unclassified drug
Article
Cloning
Enzyme activation
Enzyme binding
Enzyme conformation
Enzyme structure
Fluorescence spectroscopy
Heteronuclear single quantum coherence
Human
Immune response
Mutational analysis
Nonhuman
Nuclear magnetic resonance
Nucleotide sequence
Priority journal
Protein expression
Protein interaction
Protein purification
Saccharomyces cerevisiae
Signal transduction
Surface plasmon resonance
Tollip c2 structure
Calcium
Gene Expression Regulation
Humans
Intracellular Signaling Peptides and Proteins
Kinetics
Mutation
Phosphatidylinositols
Protein Binding
Protein Structure, Tertiary
Protein Transport
Saccharomyces cerevisiae
Interleukin 1 receptor associated kinase
Liposome
Phosphatidylinositol 3 phosphate
Phosphatidylinositol 4,5 bisphosphate
Synaptotagmin
Toll like receptor
Tollip
Unclassified drug
Article
Cloning
Enzyme activation
Enzyme binding
Enzyme conformation
Enzyme structure
Fluorescence spectroscopy
Heteronuclear single quantum coherence
Human
Immune response
Mutational analysis
Nonhuman
Nuclear magnetic resonance
Nucleotide sequence
Priority journal
Protein expression
Protein interaction
Protein purification
Saccharomyces cerevisiae
Signal transduction
Surface plasmon resonance
Tollip c2 structure
Calcium
Gene Expression Regulation
Humans
Intracellular Signaling Peptides and Proteins
Kinetics
Mutation
Phosphatidylinositols
Protein Binding
Protein Structure, Tertiary
Protein Transport
Saccharomyces cerevisiae