title: Tumour-associated mutations of PA-TM-RING ubiquitin ligases RNF167/RNF13 identify the PA domain as a determinant for endosomal localization.
abstract: Diverse cellular processes depend on endocytosis, intracellular vesicle trafficking, sorting and exocytosis, and processes that are regulated post-transcriptionally by modifications such as phosphorylation and ubiquitylation. The PA (protease-associated) domain E3 ligases, such as GodzillaCG10277 in Drosophila melanogaster and RNF167 (RING finger protein 167) in humans, have been implicated in the regulation of cellular endosome trafficking. In the present study, we have characterized point mutations in the RING (really interesting new gene) domain of human RNF13 and RNF167, which have been identified in human tumour samples, that abrogate ubiquitin ligase activity as well as function. In the present study, we have also identified a functional role for the PA domain, which is required for endosomal localization of these proteins. Although the PA domain point mutations of RNF13 and RNF167 identified in human tumours are ligase active, the resultant mutant proteins are mislocalized within the cell. Thus the PA domain E3 ligases examined in the present study appear to require both E3 ligase activity as well as an intact PA domain to efficiently target and ubiquitylate their cellular substrates.
authors.affiliation: *Department of Molecular Biology, Umeå University, 90187 Umeå, Sweden.
authors.forename: Jesper R
authors.initials: JR
authors.lastname: van Dijk
authors.affiliation: *Department of Molecular Biology, Umeå University, 90187 Umeå, Sweden.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yamazaki
authors.affiliation: *Department of Molecular Biology, Umeå University, 90187 Umeå, Sweden.
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Palmer
mesh_terms: D000595:Amino Acid Sequence; D014408:Biomarkers, Tumor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D006023:Glycoproteins; C540080:RNF13 protein, human; C108062:TTC3 protein, human; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases