Positive selection of cereblon modified function including its E3 ubiquitin ligase activity and binding efficiency with AMPK
| Autor: | Toru Asahi, Naoya Sawamura, Wataru Onodera |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0106 biological sciences
0301 basic medicine Ubiquitin-Protein Ligases AMP-Activated Protein Kinases 010603 evolutionary biology 01 natural sciences Evolution Molecular Serine 03 medical and health sciences Ubiquitin Molecular evolution Cell Line Tumor Genetics Animals Humans Selection Genetic Codon Protein kinase A Molecular Biology Phylogeny Ecology Evolution Behavior and Systematics Mammals Multiple sequence alignment biology Cereblon Ubiquitination Ubiquitin ligase Cell biology 030104 developmental biology Mutation biology.protein Function (biology) Peptide Hydrolases Protein Binding |
| Zdroj: | Molecular Phylogenetics and Evolution. 135:78-85 |
| ISSN: | 1055-7903 |
| Popis: | Cereblon (CRBN) is a substrate receptor for an E3 ubiquitin ligase that directly binds to target proteins resulting in cellular activities, such as energy metabolism, membrane potential regulation, and transcription factor degradation. Genetic mutations in human CRBN lead to intellectual disabilities. In addition, it draws pathological attention because direct binding with immunomodulatory drugs can cure multiple myeloma (MM) and lymphocytic leukemia. To further explore the function of CRBN, we focused on its molecular evolution. Since CRBN interacts directly with its substrates and is widely conserved in vertebrates, evolutionary study to identify the selective pressure on CRBN that occur during CRBN-substrate interaction is an effective approach to search for a novel active site. Using mammalian CRBN sequences, dN/dS analysis was conducted to detect positive selection. By multiple sequence alignment we found that the residue at position 366 was under positive selection. This residue is present in the substrate-binding domain of CRBN. Most mammals harbor cysteine at position 366, whereas rodents and chiroptera have serine at this site. Subsequently, we constructed a C366S human CRBN to confirm the potential of positive selection. Auto-ubiquitination activity occurs in E3 ubiquitin ligases, including CRBN, and increased in C366S CRBN, which lead to the conclusion that E3 ubiquitin ligase activity may have changed over the course of mammalian evolution. Furthermore, binding with AMP-activated protein kinase was augmented when the substitution was present, which is supported by coevolution analysis. These results suggest that the molecular evolution of CRBN occurred through codon-based positive selection, providing a new approach to investigate CRBN function. |
| Databáze: | OpenAIRE |
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