Human DNA-Damage-Inducible 2 Protein Is Structurally and Functionally Distinct from Its Yeast Ortholog

0463511 - ÚOCHB 2017 RIV GB eng J - Článek v odborném periodiku
Sivá, Monika - Svoboda, Michal - Veverka, Václav - Trempe, J. F. - Hofmann, K. - Kožíšek, Milan - Hexnerová, Rozálie - Sedlák, František - Belza, Jan - Brynda, Jiří - Šácha, Pavel - Hubálek, Martin - Starková, Jana - Flaisigová, Iva - Konvalinka, Jan - Grantz Šašková, Klára
Human DNA-Damage-Inducible 2 Protein Is Structurally and Functionally Distinct from Its Yeast Ortholog.
Scientific Reports. Roč. 6, Jul 27 (2016), č. článku 30443. ISSN 2045-2322. E-ISSN 2045-2322
Grant CEP: GA ČR(CZ) GBP208/12/G016
Institucionální podpora: RVO:61388963
Klíčová slova: human DNA-damage-inducible 2 protein * proteasome * ubiquitin * retroviral protease-like domain
Kód oboru RIV: CE - Biochemie
Impakt faktor: 4.259, rok: 2016
http://www.nature.com/articles/srep30443

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.
Trvalý link: http://hdl.handle.net/11104/0262688