Discoidin domain receptor functions in physiological and pathological conditions.
Gene Ontology annotation through association of InterPro records with GO terms
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Automatic assignment of GO terms using logical inference, based on on inter-ontology links
Discoidin domain receptor regulates ensheathment, survival and caliber of peripheral axons.
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An in vivo RNAi screen in peripheral wrapping glia identified Ddr as required for axon ensheathment.
"In an in vivo RNA interference screen to identify glial genes required for axon ensheathment, we identified the conserved receptor tyrosine kinase Discoidin domain receptor (Ddr)."
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CRISPR null alleles of Ddr are viable; the locus encodes a 1054-aa receptor and a 380-aa short isoform lacking the transmembrane and kinase regions.
"Ddr encodes two potential isoforms: a short isoform (380 amino acids) that lacks transmembrane and kinase domains, and a full-length isoform that encodes a 1054 amino acid protein."
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Mutant ensheathment defects are rescued by Ddr expressed only in wrapping glia.
"Similar phenotypes were observed in Ddr loss-of-function animals and could be rescued by resupplying Ddr specifically in wrapping glia, confirming the specificity of our RNAi results."
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In adult wing nerves, loss of Ddr reduces long-term sensory neuron survival and axon caliber without overt ensheathment defects.
"In adult nerves, loss of Ddr decreased long-term survival of sensory neurons and significantly reduced axon caliber without overtly affecting ensheathment."
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Ddr and the collagen Multiplexin interact genetically (double heterozygotes); Mp is proposed, not shown, to be a Ddr ligand.
"the strong genetic interaction we observed between Ddr and Mp is consistent with a model in which Mp acts as a collagen ligand for Ddr during axonal ensheathment"
Crystallographic insight into collagen recognition by discoidin domain receptor 2.
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The DDR2 discoidin domain binds collagen through an amphiphilic pocket lined by Trp52, Thr56, the Cys73-Cys177 disulfide, Asp69, Arg105, Glu113 and Asn175.
"One wall and the floor of the pocket are essentially apolar (Trp52, Thr56, and Cys73-Cys177 disulfide bridge), whereas the other wall is dominated by three charged residues (Asp69, Arg105, and Glu113) interacting with a string of water molecules."
Cross species systems biology discovers glial DDR2, STOM, and KANK2 as therapeutic targets in progressive supranuclear palsy.
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RNAi of the fly DDR2 orthologue modified tau neurotoxicity in a Drosophila eye model.
"Nevertheless one of the top prioritized genes DDR2, has congruent findings in Drosophila when suppressed with RNAi as in other in vitro and in vivo models"
Ddr (Q59DZ7) bioinformatics: collagen-pocket and kinase catalytic residues
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Dipteran Ddr (D. melanogaster, D. virilis, Anopheles) has lost the beta3 lysine, catalytic-loop asparagine and DFG aspartate; Tribolium DDR and C. elegans ddr-2 keep all three, the Apis model keeps two (no beta3 lysine) and C. elegans ddr-1 one (the catalytic-loop asparagine).
"Dipteran Ddr is therefore predicted to be a pseudokinase"
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The vertebrate DDR collagen-binding pocket residues Trp52 and Asp69 are not conserved in fly Ddr or other invertebrate DDRs.
"The pocket that recognises the GVMGFO motif of fibrillar collagens in vertebrates is thus not conserved in invertebrates"
UniProtKB Q59DZ7 entry (Ddr, Drosophila melanogaster)
Ddr curation notes and literature search log
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Manual PubMed and web searches found PMID:36355066 as the only functional study of fly Ddr; olfactory, wound and basement-membrane leads were not found.
"They are not used in the review."