Nemo6 - Structure, Function and Evolution of Nme6/Nm23-H6 Protein
Nucleoside-diphosphate kinases (Nme/Nm23/NDPK) constitute a family of evolutionary conserved enzymes involved in many crucial biological processes. Despite of intensive studies in the last two decades, their biochemical functions have not yet been fully elucidated. The family consists of ten members divided in two groups. Group I, which encompasses Nme1-Nme4, has been extensively studied, especially Nme1 in the context of metastasis formation and Nme2 which appears to be involved in cardiac diseases. The Group I members in humans are generally highly homologous among themselves and in comparison to their orthologues in other Metazoans. They all possess the NDP kinase activity in their hexameric form. The Group II members display a lower level of mutual homology and, with a possible exception of Nme6, apparently do not possess the NDP kinase activity. Their multimeric structure has not yet been revealed. The Group II members are evolutionary older, especially the Nme5, Nme6 and Nme7. Numerous proteins from evolutionary distinct organisms exhibit extraordinary similarity in primary structure with their orthologues in mammals including humans, as do their predicted secondary and tertiary structures. Therefore, it is presumed that they have similar or identical biochemical and biological functions. Sponges are regarded to be living fossils, and it is widely accepted that their genome and proteome structure did not change much in the last 500 million years. Therefore, they have probably preserved the genome and proteome structure of the common ancestor of all Metazoans. Our results on sponge Nme genes/proteins show that NmeGpISd, the single member of the Group I from marine sponge Suberites domuncula, probably reflects the characteristics of the ancestral Group I Nme genes/proteins, which existed prior to the duplication of this group in vertebrates and other lineages. On the contrary, the results of our studies on Nme6Sd suggest that the sponge protein has different cellular functions from its human orthologue. Building upon our previous work on the human and sponge Nme family proteins, the proposed project will focus on resolving the structure, as well as biochemical and biological functions of the human Nme6 and its changes during evolution. We will employ a range of biochemical methods and combine them with modern molecular biology methods supported by advanced confocal microscopy techniques. We will attempt to 1) clarify the potential NDP kinase activity and the quaternary structure of Nme6; 2) unravel its involvement in crucial cellular physiological processes; 3) define the subcellular localization of Nme6; 4) identify the possible interacting partners of Nme6, with a focus on the Nme Group I proteins, and the intracellular location of their interaction. We are confident that our research on the Nme6 protein will provide new insights into this protein family in general and the role of its members in major human diseases.
1. Ćetković H, Harcet M, Roller M, Herak Bosnar M*. A survey of metastasis suppressors in Metazoa. Laboratory Investigation 2018, Laboratory Investigation 98, 554–570,2018
2. Herak Bosnar M*, Radić M, Ćetković H. A young researcher’s guide to NME/Nm23/NDP Kinase Periodicum biologorum 120, 3-9, 2018
3. Ćetković H+, Halasz M+, Herak Bosnar M+: Sponges: A Reservoir of Genes Implicated in Human Cancer. Marine Drugs, Marine Drugs , 16(1), 20, 2018
4. Ćetković H, Herak Bosnar M, Perina D, Mikoč A, Deželjin M, Belužić R, Bilandžija H, Ruiz-Trillo I, Harcet M. Characterization of a group I Nme protein of Capsaspora owczarzaki—a close unicellular relative of animals, Laboratory Investigation 98, 304–314, 2018
Dr. sc. Uwe Schlatner, Université Grenoble Alpes, France