UniProt functional annotation for P08953



	UniProt functional annotation for P08953

UniProt code: P08953.

Organism: Drosophila melanogaster (Fruit fly).

Taxonomy: Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota; Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; Ephydroidea; Drosophilidae; Drosophila; Sophophora.

Function: Receptor for the cleaved activated form of spz, spaetzle C- 106 (PubMed:12872120). Binding to spaetzle C-106 activates the Toll signaling pathway and induces expression of the antifungal peptide drosomycin (PubMed:12872120, PubMed:8808632, PubMed:10973475). Component of the extracellular signaling pathway that establishes dorsal-ventral polarity in the embryo (PubMed:3931919). Promotes heterophilic cellular adhesion (PubMed:2124970). Involved in synaptic targeting of motoneurons RP5 and V to muscle 12 (M12); functions as a repulsive cue inhibiting motoneuron synapse formation on muscle 13 (M13) to guide RP5 and V to the neighboring M12, where its expression is repressed by tey (PubMed:20504957). May also function in embryonic neuronal survival and the synaptic targeting of SNa motoneurons (PubMed:19018662). {ECO:0000269|PubMed:10973475, ECO:0000269|PubMed:12872120, ECO:0000269|PubMed:19018662, ECO:0000269|PubMed:20504957, ECO:0000269|PubMed:2124970, ECO:0000269|PubMed:3931919, ECO:0000269|PubMed:8808632}.

Catalytic activity: Reaction=H2O + NAD(+) = ADP-D-ribose + H(+) + nicotinamide; Xref=Rhea:RHEA:16301, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:17154, ChEBI:CHEBI:57540, ChEBI:CHEBI:57967; EC=3.2.2.6; Evidence={ECO:0000255|PROSITE-ProRule:PRU00204}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16302; Evidence={ECO:0000255|PROSITE-ProRule:PRU00204};

Subunit: In the absence of ligand, forms a low-affinity disulfide- linked homodimer (PubMed:24733933). In the presence of ligand, crystal structures show one Tl molecule bound to a spaetzle C-106 homodimer (PubMed:24282309, PubMed:24733933). However, the active complex probably consists of two Tl molecules bound to a spaetzle C-106 homodimer (PubMed:24282309, PubMed:24733933). This is supported by in vitro experiments which also show binding of the spaetzle C-106 dimer to 2 Tl receptors (PubMed:12872120). Ligand binding induces conformational changes in the extracellular domain of Tl (PubMed:24282309). This may enable a secondary homodimerization interface at the C-terminus of the Tl extracellular domain (PubMed:24282309). {ECO:0000269|PubMed:12872120, ECO:0000269|PubMed:24282309, ECO:0000269|PubMed:24733933, ECO:0000303|PubMed:24282309}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:15373972, ECO:0000269|PubMed:1879347}; Single-pass type I membrane protein {ECO:0000255}. Cytoplasm {ECO:0000269|PubMed:15373972}. Note=In the fat body, detected in puntate structures along the cell periphery. Becomes evenly distributed in the cytoplasm 1 hour after bacterial infection. {ECO:0000269|PubMed:15373972}.

Tissue specificity: In early embryos, concentrated in the pseudocleavage furrows that form transiently between nuclei before cellularization and in the cleavage furrows during cellularization (at protein level) (PubMed:1879347). Later, found on cells in the mesectoderm, stomodeum, proctodeum, anterior and posterior midguts, splanchnopleura, salivary gland placode and adjacent to the segmentally repeated tracheal placodes (at protein level) (PubMed:1879347). During and after germ band shortening, localized in a number of cell types, including the salivary gland, foregut, hindgut, Malpighian tubules and epidermis (at protein level) (PubMed:1879347). In embryos, high expression in M13 with comparatively low expression in M12 (PubMed:20504957). {ECO:0000269|PubMed:1879347, ECO:0000269|PubMed:20504957}.

Developmental stage: Expressed both maternally and zygotically (PubMed:2449285, PubMed:1879347, PubMed:12617819). Maternal Tl increases in syncytial embryos, reaching a peak at the syncytial blastoderm stage and then decreases and is almost undetectable by the time of ventral furrow formation at gastrulation (at protein level) (PubMed:1879347). Expressed throughout development, with highest levels of expression in the embryo (PubMed:10973475). Expressed in all embryonic central nervous system axons (PubMed:19018662). In larvae, detected in the blood cells and fat body (PubMed:12617819). {ECO:0000269|PubMed:10973475, ECO:0000269|PubMed:12617819, ECO:0000269|PubMed:1879347, ECO:0000269|PubMed:19018662, ECO:0000269|PubMed:2449285}.

Induction: Up-regulated during vesicular stomatitis virus (VSV) infection. {ECO:0000269|PubMed:22464169}.

Domain: The TIR domain mediates NAD(+) hydrolase (NADase) activity. Self-association of TIR domains is required for NADase activity. {ECO:0000255|PROSITE-ProRule:PRU00204}.

Similarity: Belongs to the Toll-like receptor family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Drosophila melanogaster (Fruit fly).
Taxonomy:		Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota; Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; Ephydroidea; Drosophilidae; Drosophila; Sophophora.



Function:		Receptor for the cleaved activated form of spz, spaetzle C- 106 (PubMed:12872120). Binding to spaetzle C-106 activates the Toll signaling pathway and induces expression of the antifungal peptide drosomycin (PubMed:12872120, PubMed:8808632, PubMed:10973475). Component of the extracellular signaling pathway that establishes dorsal-ventral polarity in the embryo (PubMed:3931919). Promotes heterophilic cellular adhesion (PubMed:2124970). Involved in synaptic targeting of motoneurons RP5 and V to muscle 12 (M12); functions as a repulsive cue inhibiting motoneuron synapse formation on muscle 13 (M13) to guide RP5 and V to the neighboring M12, where its expression is repressed by tey (PubMed:20504957). May also function in embryonic neuronal survival and the synaptic targeting of SNa motoneurons (PubMed:19018662). {ECO:0000269\|PubMed:10973475, ECO:0000269\|PubMed:12872120, ECO:0000269\|PubMed:19018662, ECO:0000269\|PubMed:20504957, ECO:0000269\|PubMed:2124970, ECO:0000269\|PubMed:3931919, ECO:0000269\|PubMed:8808632}.


Catalytic activity:		Reaction=H2O + NAD(+) = ADP-D-ribose + H(+) + nicotinamide; Xref=Rhea:RHEA:16301, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:17154, ChEBI:CHEBI:57540, ChEBI:CHEBI:57967; EC=3.2.2.6; Evidence={ECO:0000255\|PROSITE-ProRule:PRU00204}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16302; Evidence={ECO:0000255\|PROSITE-ProRule:PRU00204};
Subunit:		In the absence of ligand, forms a low-affinity disulfide- linked homodimer (PubMed:24733933). In the presence of ligand, crystal structures show one Tl molecule bound to a spaetzle C-106 homodimer (PubMed:24282309, PubMed:24733933). However, the active complex probably consists of two Tl molecules bound to a spaetzle C-106 homodimer (PubMed:24282309, PubMed:24733933). This is supported by in vitro experiments which also show binding of the spaetzle C-106 dimer to 2 Tl receptors (PubMed:12872120). Ligand binding induces conformational changes in the extracellular domain of Tl (PubMed:24282309). This may enable a secondary homodimerization interface at the C-terminus of the Tl extracellular domain (PubMed:24282309). {ECO:0000269\|PubMed:12872120, ECO:0000269\|PubMed:24282309, ECO:0000269\|PubMed:24733933, ECO:0000303\|PubMed:24282309}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:15373972, ECO:0000269\|PubMed:1879347}; Single-pass type I membrane protein {ECO:0000255}. Cytoplasm {ECO:0000269\|PubMed:15373972}. Note=In the fat body, detected in puntate structures along the cell periphery. Becomes evenly distributed in the cytoplasm 1 hour after bacterial infection. {ECO:0000269\|PubMed:15373972}.
Tissue specificity:		In early embryos, concentrated in the pseudocleavage furrows that form transiently between nuclei before cellularization and in the cleavage furrows during cellularization (at protein level) (PubMed:1879347). Later, found on cells in the mesectoderm, stomodeum, proctodeum, anterior and posterior midguts, splanchnopleura, salivary gland placode and adjacent to the segmentally repeated tracheal placodes (at protein level) (PubMed:1879347). During and after germ band shortening, localized in a number of cell types, including the salivary gland, foregut, hindgut, Malpighian tubules and epidermis (at protein level) (PubMed:1879347). In embryos, high expression in M13 with comparatively low expression in M12 (PubMed:20504957). {ECO:0000269\|PubMed:1879347, ECO:0000269\|PubMed:20504957}.
Developmental stage:		Expressed both maternally and zygotically (PubMed:2449285, PubMed:1879347, PubMed:12617819). Maternal Tl increases in syncytial embryos, reaching a peak at the syncytial blastoderm stage and then decreases and is almost undetectable by the time of ventral furrow formation at gastrulation (at protein level) (PubMed:1879347). Expressed throughout development, with highest levels of expression in the embryo (PubMed:10973475). Expressed in all embryonic central nervous system axons (PubMed:19018662). In larvae, detected in the blood cells and fat body (PubMed:12617819). {ECO:0000269\|PubMed:10973475, ECO:0000269\|PubMed:12617819, ECO:0000269\|PubMed:1879347, ECO:0000269\|PubMed:19018662, ECO:0000269\|PubMed:2449285}.
Induction:		Up-regulated during vesicular stomatitis virus (VSV) infection. {ECO:0000269\|PubMed:22464169}.
Domain:		The TIR domain mediates NAD(+) hydrolase (NADase) activity. Self-association of TIR domains is required for NADase activity. {ECO:0000255\|PROSITE-ProRule:PRU00204}.
Similarity:		Belongs to the Toll-like receptor family. {ECO:0000305}.