Human DNA-Damage-Inducible 2 Protein Is Structurally and Functionally Distinct from Its Yeast Ortholog
| Autor: | Jean-François Trempe, Kay Hofmann, Pavel Šácha, Iva Flaisigová, Rozálie Hexnerová, Klára Grantz Šašková, Jiří Brynda, Jan Konvalinka, Michal Svoboda, Jan Belza, Monika Sivá, Milan Kožíšek, Jana Starková, Martin Hubálek, Vaclav Veverka, Frantisek Sedlak |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Models Molecular Aspartic Acid Proteases Saccharomyces cerevisiae Proteins Saccharomyces cerevisiae Protein domain Amino Acid Motifs Plasma protein binding Crystallography X-Ray Article Conserved sequence Evolution Molecular 03 medical and health sciences 0302 clinical medicine Ubiquitin Protein Domains Sequence Analysis Protein Protein Interaction Mapping Scattering Small Angle Humans Amino Acid Sequence Polyubiquitin Peptide sequence Conserved Sequence Multidisciplinary biology HEK 293 cells biology.organism_classification Yeast Cell biology Solutions 030104 developmental biology HEK293 Cells Biochemistry Structural Homology Protein 030220 oncology & carcinogenesis Proteolysis biology.protein Protein Multimerization Protein Binding |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | Although Ddi1-like proteins are conserved among eukaryotes, their biological functions remain poorly characterized. Yeast Ddi1 has been implicated in cell cycle regulation, DNA-damage response and exocytosis. By virtue of its ubiquitin-like (UBL) and ubiquitin-associated (UBA) domains, it has been proposed to serve as a proteasomal shuttle factor. All Ddi1-like family members also contain a highly conserved retroviral protease-like (RVP) domain with unknown substrate specificity. While the structure and biological function of yeast Ddi1 have been investigated, no such analysis is available for the human homologs. To address this, we solved the 3D structures of the human Ddi2 UBL and RVP domains and identified a new helical domain that extends on either side of the RVP dimer. While Ddi1-like proteins from all vertebrates lack a UBA domain, we identify a novel ubiquitin-interacting motif (UIM) located at the C-terminus of the protein. The UIM showed a weak yet specific affinity towards ubiquitin, as did the Ddi2 UBL domain. However, the full-length Ddi2 protein is unable to bind to di-ubiquitin chains. While proteomic analysis revealed no activity, implying that the protease requires other factors for activation, our structural characterization of all domains of human Ddi2 sets the stage for further characterization. |
| Databáze: | OpenAIRE |
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