Positive Selection of Cereblon Modified Function Including its E3 Ubiquitin Ligase Activity and Binding Efficiency with AMPK

Publication date: Available online 2 March 2019Source: Molecular Phylogenetics and EvolutionAuthor(s): Wataru Onodera, Toru Asahi, Naoya SawamuraAbstractCereblon (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 C3...

Source: Molecular Phylogenetics and Evolution - March 4, 2019 Category: Molecular Biology Source Type: research