Annotation inferences using phylogenetic trees
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
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The study generated a neurodegenerative-disease-centered interaction network by systematic yeast two-hybrid screening, making its LONRF2 interactions candidate binary associations rather than demonstrated substrates.
"Here, we report on an interactome map that focuses on neurodegenerative disease (ND), connects ∼5,000 human proteins via ∼30,000 candidate interactions and is generated by systematic yeast two-hybrid interaction screening of ∼500 ND-related proteins and integration of literature interactions."
LONRF2 is a protein quality control ubiquitin ligase whose deficiency causes late-onset neurological deficits.
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LONRF2 is a protein-quality-control ubiquitin ligase induced in post-mitotic senescent cells and predominantly expressed in neurons under unperturbed conditions.
"Here, we show that LONRF2 is a bona fide protein quality control ubiquitin ligase induced in post-mitotic senescent cells. Under unperturbed conditions, LONRF2 is predominantly expressed in neurons."
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LONRF2 recognizes and ubiquitylates structurally abnormal RNA-binding proteins and artificial misfolded substrates.
"LONRF2 binds and ubiquitylates abnormally structured TDP-43 and hnRNP M1 and artificially misfolded proteins."
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Loss of Lonrf2 causes age-dependent motor-neuron degeneration and cerebellar ataxia in mice.
"Lonrf2-/- mice exhibit age-dependent TDP-43-mediated motor neuron (MN) degeneration and cerebellar ataxia."
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LONRF2 loss impairs motor-neuron survival and neurite maintenance and permits accumulation of pathological protein assemblies.
"Mouse induced pluripotent stem cell-derived MNs lacking LONRF2 showed reduced survival, shortening of neurites and accumulation of pTDP-43 and G3BP1 after long-term culture."
The ubiquitin ligase LONRF2 inhibits glycolysis and malignant phenotypes in endometrial cancer through aldolase a degradation.
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ALDOA was identified as a LONRF2 interaction partner by immunoprecipitation and mass spectrometry.
"Aldolase A (ALDOA) was identified as a LONRF2-interacting protein via immunoprecipitation and nano-liquid chromatography-tandem mass spectrometry."
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LONRF2 promotes ALDOA ubiquitylation and degradation.
"LONRF2 interacted with ALDOA and induced its ubiquitination and degradation."
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In endometrial cancer cells, LONRF2 overexpression suppresses growth, glycolysis, migration and invasion.
"LONRF2 overexpression inhibited the growth, glycolysis, migration, and invasion of KLE cells."
LONRF2 comparative domain analysis results
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LONRF2 lacks the AAA+ ATPase and protease machinery that defines an active Lon peptidase, despite retaining a Lon N-terminal substrate-binding-domain homolog.
"More decisively, the targeted presence matrix finds no AAA+ ATPase domain/core (IPR003593/IPR003959), Lon protease family call (IPR004815), peptidase S16 active site (IPR008268), or Lon proteolytic domain (IPR008269) in LONRF2. All five are present in the LONP1 control."
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The C-terminal RING call is strongly supported, whereas the N-terminal RING-like call remains structurally and biochemically unresolved.
"Thus, this workflow does not establish that the first broad call is an intact canonical zinc-coordinating RING; it may be atypical or degenerate and would require structural or biochemical validation."
UniProtKB entry Q1L5Z9 (LONF2_HUMAN)